Pub Date : 2024-12-13DOI: 10.1038/s12276-024-01359-z
Sun-Min Lee, M. Azim Surani
Primordial germ cells (PGCs) are the precursors of sperm and eggs. They undergo genome-wide epigenetic reprogramming to erase epigenetic memory and reset the genomic potential for totipotency. Global DNA methylation erasure is a crucial part of epigenetic resetting when DNA methylation levels decrease across the genome to <5%. However, certain localized regions exhibit slower demethylation or resistance to reprogramming. Since DNA methylation plays a crucial role in transcriptional regulation, this depletion in PGCs requires mechanisms independent of DNA methylation to regulate transcriptional control during PGC reprogramming. Histone modifications are predicted to compensate for the loss of DNA methylation in gene regulation. Different histone modifications exhibit distinct patterns in PGCs undergoing epigenetic programming at the genomic level during PGC development in conjunction with changes in DNA methylation. Together, they contribute to PGC-specific genomic regulation. Recent findings related to these processes provide a comprehensive overview of germline epigenetic reprogramming and its importance in mouse and human PGC development. Additionally, we evaluated the extent to which in vitro culture techniques have replicated the development processes of human PGCs. Primordial germ cells (PGCs), which eventually become eggs or sperm, undergo unique and important changes early in their development that are crucial for forming a complete organism after fertilization. Recent studies have advanced our understanding of these changes. This review explains how certain processes, such as adding chemical markers to DNA (DNA methylation) and modifying proteins around DNA (histone modifications), control the development of PGCs in humans and mice. It also explores the replication of these processes in the lab using human stem cells. This review provides important insights into the impact of these changes on reproduction and offers potential new avenues for treating infertility. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Epigenetic reprogramming in mouse and human primordial germ cells","authors":"Sun-Min Lee, M. Azim Surani","doi":"10.1038/s12276-024-01359-z","DOIUrl":"10.1038/s12276-024-01359-z","url":null,"abstract":"Primordial germ cells (PGCs) are the precursors of sperm and eggs. They undergo genome-wide epigenetic reprogramming to erase epigenetic memory and reset the genomic potential for totipotency. Global DNA methylation erasure is a crucial part of epigenetic resetting when DNA methylation levels decrease across the genome to <5%. However, certain localized regions exhibit slower demethylation or resistance to reprogramming. Since DNA methylation plays a crucial role in transcriptional regulation, this depletion in PGCs requires mechanisms independent of DNA methylation to regulate transcriptional control during PGC reprogramming. Histone modifications are predicted to compensate for the loss of DNA methylation in gene regulation. Different histone modifications exhibit distinct patterns in PGCs undergoing epigenetic programming at the genomic level during PGC development in conjunction with changes in DNA methylation. Together, they contribute to PGC-specific genomic regulation. Recent findings related to these processes provide a comprehensive overview of germline epigenetic reprogramming and its importance in mouse and human PGC development. Additionally, we evaluated the extent to which in vitro culture techniques have replicated the development processes of human PGCs. Primordial germ cells (PGCs), which eventually become eggs or sperm, undergo unique and important changes early in their development that are crucial for forming a complete organism after fertilization. Recent studies have advanced our understanding of these changes. This review explains how certain processes, such as adding chemical markers to DNA (DNA methylation) and modifying proteins around DNA (histone modifications), control the development of PGCs in humans and mice. It also explores the replication of these processes in the lab using human stem cells. This review provides important insights into the impact of these changes on reproduction and offers potential new avenues for treating infertility. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2578-2587"},"PeriodicalIF":9.5,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01359-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-13DOI: 10.1038/s12276-024-01367-z
Hyun-Seung Lee, Byung-Keun Kim, Suh-Young Lee, Hyuktae Kwon, Heung-Woo Park
A high-fat diet (HFD) can induce airway hyperresponsiveness (AHR) in obese mice, independent of allergic sensitization. This study aimed to identify the key molecules related to AHR in HFD-induced obese mice. In a cluster analysis of time series gene expression in the adipose and lung tissues of HFD-induced obese mice, we identified the Caspase Recruitment Domain Family Member 11 (Card11) gene as an essential molecule. We measured CARD11 expression in peripheral blood mononuclear cells (PBMCs) from obese individuals with asthma and performed Card11 signal inhibition in HFD-induced obese mice via Card11 siRNA. Card11 expression was significantly increased in M1 macrophages (IL-1β+CD11c+CD206- in CD11b+) in adipose tissue and in ILC3s (RORγt+ in IL7R+ of Lin-) in lung tissue from HFD-induced obese mice. In addition, CARD11+ populations among ILC3s and LPS-stimulated IL-1β+CD16+ monocytes from the PBMCs of obese individuals with asthma were significantly greater than those from obese controls or nonobese individuals with asthma. AHR in HFD-induced obese mice disappeared when we inhibited the Card11 signaling pathway by administering Card11 siRNA during the first or last seven weeks of the 13-week HFD feeding. Finally, we confirmed that Card11 siRNA decreased the number of M1 macrophages in adipose tissue and the number of ILC3s in lung tissue in vitro. Card11 significantly contributes to the development of AHR in HFD-induced obese mice by affecting immune cells in both adipose and lung tissues. The middle stage of HFD feeding seemed to be critical for these processes. Obesity is a metabolic disease and a major risk factor for several non-communicable diseases. The link between obesity and asthma is not fully understood. The study used a murine model to investigate how obesity affects asthma. Researchers fed mice a high-fat diet and analyzed gene expression in their adipose and lung tissues. They identified the Card11 gene as a key player in airway hyperresponsiveness in obese mice. This was an experimental study involving mice. Results showed that Card11 expression increased in immune cells from both adipose and lung tissues of obese mice. Inhibiting Card11 reduced AHR and inflammation. Researchers concluded that Card11 is crucial in obesity-related asthma. Future studies could explore Card11 as a therapeutic target for asthma in obese individuals. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Essential role of Card11 in airway hyperresponsiveness in high-fat diet-induced obese mice","authors":"Hyun-Seung Lee, Byung-Keun Kim, Suh-Young Lee, Hyuktae Kwon, Heung-Woo Park","doi":"10.1038/s12276-024-01367-z","DOIUrl":"10.1038/s12276-024-01367-z","url":null,"abstract":"A high-fat diet (HFD) can induce airway hyperresponsiveness (AHR) in obese mice, independent of allergic sensitization. This study aimed to identify the key molecules related to AHR in HFD-induced obese mice. In a cluster analysis of time series gene expression in the adipose and lung tissues of HFD-induced obese mice, we identified the Caspase Recruitment Domain Family Member 11 (Card11) gene as an essential molecule. We measured CARD11 expression in peripheral blood mononuclear cells (PBMCs) from obese individuals with asthma and performed Card11 signal inhibition in HFD-induced obese mice via Card11 siRNA. Card11 expression was significantly increased in M1 macrophages (IL-1β+CD11c+CD206- in CD11b+) in adipose tissue and in ILC3s (RORγt+ in IL7R+ of Lin-) in lung tissue from HFD-induced obese mice. In addition, CARD11+ populations among ILC3s and LPS-stimulated IL-1β+CD16+ monocytes from the PBMCs of obese individuals with asthma were significantly greater than those from obese controls or nonobese individuals with asthma. AHR in HFD-induced obese mice disappeared when we inhibited the Card11 signaling pathway by administering Card11 siRNA during the first or last seven weeks of the 13-week HFD feeding. Finally, we confirmed that Card11 siRNA decreased the number of M1 macrophages in adipose tissue and the number of ILC3s in lung tissue in vitro. Card11 significantly contributes to the development of AHR in HFD-induced obese mice by affecting immune cells in both adipose and lung tissues. The middle stage of HFD feeding seemed to be critical for these processes. Obesity is a metabolic disease and a major risk factor for several non-communicable diseases. The link between obesity and asthma is not fully understood. The study used a murine model to investigate how obesity affects asthma. Researchers fed mice a high-fat diet and analyzed gene expression in their adipose and lung tissues. They identified the Card11 gene as a key player in airway hyperresponsiveness in obese mice. This was an experimental study involving mice. Results showed that Card11 expression increased in immune cells from both adipose and lung tissues of obese mice. Inhibiting Card11 reduced AHR and inflammation. Researchers concluded that Card11 is crucial in obesity-related asthma. Future studies could explore Card11 as a therapeutic target for asthma in obese individuals. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2747-2754"},"PeriodicalIF":9.5,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01367-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-06DOI: 10.1038/s12276-024-01366-0
Ha Yeon Jeong, Jin-Sil Park, Jeong Won Choi, Kun Hee Lee, Seung Cheon Yang, Hye Yeon Kang, Sang Hee Cho, Seon-Yeong Lee, A Ram Lee, Youngjae Park, Sung-Hwan Park, Mi-La Cho
The gene associated with the retinoid–IFN-induced mortality-19 (GRIM-19) protein is a regulator of a cell death regulatory protein that inhibits STAT3, which is a critical transcription factor for interleukin (IL)-17-producing T (Th17) cells and a key integrator of extracellular matrix accumulation in systemic sclerosis (SSc). This protein is also a component of mitochondrial complex I, where it directly binds to STAT3 and recruits STAT3 to the mitochondria via the mitochondrial importer Tom20. In this study, the role of GRIM19 and its relationship with STAT3 in SSc development was investigated using a murine model of SSc. We observed a decrease in the level of GRIM-19 in the lesional skin of mice with bleomycin-induced SSc, which was negatively correlated with the level of STAT3. Overexpression of GRIM-19 reduced dermal thickness and fibrosis and the frequency of Th2 and Th17 cells in SSc mice. Mitophagic dysfunction promoted fibrosis in mice lacking PINK1, which is a mitophagy inducer. In an in vitro system, the overexpression of GRIM-19 increased the level of mitochondrial STAT3 (mitoSTAT3), induced mitophagy, and alleviated fibrosis progression. MitoSTAT3 overexpression hindered the development of bleomycin-induced SSc by reducing fibrosis. These results suggest that GRIM-19 is an effective therapeutic target for alleviating the development of SSc by increasing mitophagy. Systemic sclerosis is an autoimmune disease causing skin and organ fibrosis. The exact cause is unknown, but inflammation plays a key role. Researchers found a gap in understanding how the GRIM-19 protein affects SSc. Ha Yeon Jeong and colleagues conducted experiments on mice to explore this. The study involved injecting mice with a substance to induce SSc and then treating them with a GRIM-19 plasmid (a small DNA molecule). This experiment aimed to see if GRIM-19 could reduce fibrosis. The study type was an experiment involving 8-week-old male mice. Results showed that overexpression of GRIM-19 reduced skin thickness and inflammation in SSc mice. The researchers concluded that GRIM-19 helps control fibrosis by interacting with mitochondrial STAT3 (a protein involved in cell signaling). Future research could explore GRIM-19 as a potential treatment for SSc. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"GRIM-19-mediated induction of mitochondrial STAT3 alleviates systemic sclerosis by inhibiting fibrosis and Th2/Th17 cells","authors":"Ha Yeon Jeong, Jin-Sil Park, Jeong Won Choi, Kun Hee Lee, Seung Cheon Yang, Hye Yeon Kang, Sang Hee Cho, Seon-Yeong Lee, A Ram Lee, Youngjae Park, Sung-Hwan Park, Mi-La Cho","doi":"10.1038/s12276-024-01366-0","DOIUrl":"10.1038/s12276-024-01366-0","url":null,"abstract":"The gene associated with the retinoid–IFN-induced mortality-19 (GRIM-19) protein is a regulator of a cell death regulatory protein that inhibits STAT3, which is a critical transcription factor for interleukin (IL)-17-producing T (Th17) cells and a key integrator of extracellular matrix accumulation in systemic sclerosis (SSc). This protein is also a component of mitochondrial complex I, where it directly binds to STAT3 and recruits STAT3 to the mitochondria via the mitochondrial importer Tom20. In this study, the role of GRIM19 and its relationship with STAT3 in SSc development was investigated using a murine model of SSc. We observed a decrease in the level of GRIM-19 in the lesional skin of mice with bleomycin-induced SSc, which was negatively correlated with the level of STAT3. Overexpression of GRIM-19 reduced dermal thickness and fibrosis and the frequency of Th2 and Th17 cells in SSc mice. Mitophagic dysfunction promoted fibrosis in mice lacking PINK1, which is a mitophagy inducer. In an in vitro system, the overexpression of GRIM-19 increased the level of mitochondrial STAT3 (mitoSTAT3), induced mitophagy, and alleviated fibrosis progression. MitoSTAT3 overexpression hindered the development of bleomycin-induced SSc by reducing fibrosis. These results suggest that GRIM-19 is an effective therapeutic target for alleviating the development of SSc by increasing mitophagy. Systemic sclerosis is an autoimmune disease causing skin and organ fibrosis. The exact cause is unknown, but inflammation plays a key role. Researchers found a gap in understanding how the GRIM-19 protein affects SSc. Ha Yeon Jeong and colleagues conducted experiments on mice to explore this. The study involved injecting mice with a substance to induce SSc and then treating them with a GRIM-19 plasmid (a small DNA molecule). This experiment aimed to see if GRIM-19 could reduce fibrosis. The study type was an experiment involving 8-week-old male mice. Results showed that overexpression of GRIM-19 reduced skin thickness and inflammation in SSc mice. The researchers concluded that GRIM-19 helps control fibrosis by interacting with mitochondrial STAT3 (a protein involved in cell signaling). Future research could explore GRIM-19 as a potential treatment for SSc. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2739-2746"},"PeriodicalIF":9.5,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01366-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-04DOI: 10.1038/s12276-024-01370-4
Sarita Saraswati, Paula Martínez, Rosa Serrano, Diego Mejías, Osvaldo Graña-Castro, Ruth Álvarez Díaz, Maria A. Blasco
{"title":"Author Correction: Renal fibroblasts are involved in fibrogenic changes in kidney fibrosis associated with dysfunctional telomeres","authors":"Sarita Saraswati, Paula Martínez, Rosa Serrano, Diego Mejías, Osvaldo Graña-Castro, Ruth Álvarez Díaz, Maria A. Blasco","doi":"10.1038/s12276-024-01370-4","DOIUrl":"10.1038/s12276-024-01370-4","url":null,"abstract":"","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2763-2763"},"PeriodicalIF":9.5,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01370-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-04DOI: 10.1038/s12276-024-01362-4
Hae Yun Nam, Seung-Ho Park, Geun-Hee Lee, Eun-Young Kim, SangEun Lee, Hyo Won Chang, Eun-Ju Chang, Kyung-Chul Choi, Seong Who Kim
TP53-induced glycolysis and apoptosis regulator (TIGAR) regulates redox homeostasis and provides the intermediates necessary for cell growth by reducing the glycolytic rate. During cellular senescence, cells undergo metabolic rewiring towards the glycolytic pathway, along with the development of the senescence-associated secretory phenotype (SASP), also known as the secretome. We observed that TIGAR expression increased during replicative senescence following the in vitro expansion of human mesenchymal stromal cells (MSCs) and that TIGAR knockout (KO) decreased SASP factors and triggered premature senescence with decelerated progression. Additionally, TIGAR KO impaired flexible lysosomal movement to the perinuclear region and decreased the autophagic flux of MSCs. Research on the mechanism of lysosomal movement revealed that, while native senescent MSCs presented low levels of Ac-α-tubulin (lysine 40) and increased sirtuin 2 (SIRT2) activity compared with those in growing cells, TIGAR KO-MSCs maintained Ac-α-tubulin levels and exhibited decreased SIRT2 activity despite being in a senescent state. The overexpression of SIRT2 reduced Ac-α-tubulin as a protein target of SIRT2 and induced the positioning of lysosomes at the perinuclear region, restoring the cytokine secretion of TIGAR KO-MSCs. Furthermore, TIGAR expression was positively correlated with SIRT2 activity, indicating that TIGAR affects SIRT2 activity partly by modulating the NAD+ level. Thus, our study demonstrated that TIGAR provides a foundation that translates the regulation of energy metabolism into lysosome positioning, affecting the secretome for senescence development. Considering the functional value of the cell-secretome in aging-related diseases, these findings suggest the feasibility of TIGAR for the regulation of secretory phenotypes. Cellular senescence is a process where cells stop dividing due to stress. Researchers found that the protein TIGAR plays a role in this process, but its exact function was unclear. In this study, researchers explored how TIGAR affects cellular senescence. They used mesenchymal stromal cells from human umbilical cord blood and conducted experiments to knock out TIGAR using CRISPR-Cas9 technology. They found that knocking out TIGAR led to early onset but slower progression of senescence. TIGAR knockout cells showed changes in lysosome positioning, reduced autophagic flux, and altered secretion of cytokines. These changes were linked to the acetylation of α-tubulin, a protein that helps in cell structure and transport. The results suggest that TIGAR regulates cellular senescence by affecting lysosome positioning and autophagy through SIRT2, an enzyme that deacetylates α-tubulin. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"TIGAR coordinates senescence-associated secretory phenotype via lysosome repositioning and α-tubulin deacetylation","authors":"Hae Yun Nam, Seung-Ho Park, Geun-Hee Lee, Eun-Young Kim, SangEun Lee, Hyo Won Chang, Eun-Ju Chang, Kyung-Chul Choi, Seong Who Kim","doi":"10.1038/s12276-024-01362-4","DOIUrl":"10.1038/s12276-024-01362-4","url":null,"abstract":"TP53-induced glycolysis and apoptosis regulator (TIGAR) regulates redox homeostasis and provides the intermediates necessary for cell growth by reducing the glycolytic rate. During cellular senescence, cells undergo metabolic rewiring towards the glycolytic pathway, along with the development of the senescence-associated secretory phenotype (SASP), also known as the secretome. We observed that TIGAR expression increased during replicative senescence following the in vitro expansion of human mesenchymal stromal cells (MSCs) and that TIGAR knockout (KO) decreased SASP factors and triggered premature senescence with decelerated progression. Additionally, TIGAR KO impaired flexible lysosomal movement to the perinuclear region and decreased the autophagic flux of MSCs. Research on the mechanism of lysosomal movement revealed that, while native senescent MSCs presented low levels of Ac-α-tubulin (lysine 40) and increased sirtuin 2 (SIRT2) activity compared with those in growing cells, TIGAR KO-MSCs maintained Ac-α-tubulin levels and exhibited decreased SIRT2 activity despite being in a senescent state. The overexpression of SIRT2 reduced Ac-α-tubulin as a protein target of SIRT2 and induced the positioning of lysosomes at the perinuclear region, restoring the cytokine secretion of TIGAR KO-MSCs. Furthermore, TIGAR expression was positively correlated with SIRT2 activity, indicating that TIGAR affects SIRT2 activity partly by modulating the NAD+ level. Thus, our study demonstrated that TIGAR provides a foundation that translates the regulation of energy metabolism into lysosome positioning, affecting the secretome for senescence development. Considering the functional value of the cell-secretome in aging-related diseases, these findings suggest the feasibility of TIGAR for the regulation of secretory phenotypes. Cellular senescence is a process where cells stop dividing due to stress. Researchers found that the protein TIGAR plays a role in this process, but its exact function was unclear. In this study, researchers explored how TIGAR affects cellular senescence. They used mesenchymal stromal cells from human umbilical cord blood and conducted experiments to knock out TIGAR using CRISPR-Cas9 technology. They found that knocking out TIGAR led to early onset but slower progression of senescence. TIGAR knockout cells showed changes in lysosome positioning, reduced autophagic flux, and altered secretion of cytokines. These changes were linked to the acetylation of α-tubulin, a protein that helps in cell structure and transport. The results suggest that TIGAR regulates cellular senescence by affecting lysosome positioning and autophagy through SIRT2, an enzyme that deacetylates α-tubulin. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2726-2738"},"PeriodicalIF":9.5,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01362-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-03DOI: 10.1038/s12276-024-01357-1
Minjeong Ko, Jiho Kim, Raudah Lazim, Ju Yeon Lee, Jin Young Kim, Vijayakumar Gosu, Yoonji Lee, Sun Choi, Ho Jeong Kwon
Metformin (MetF) is used worldwide as a first-line therapy for type 2 diabetes. Recently, interest in the pleiotropic effects of MetF, such as its anticancer and antiaging properties, has increased. However, the molecular target of MetF and the detailed mechanism underlying its ability to inhibit cell growth through autophagy induction remain incompletely understood. In this study, using an innovative label-free drug affinity responsive target stability (DARTS)-LC-MS/MS method, we discovered that mitochondrial voltage-dependent anion channel 1 (VDAC1) is a novel binding protein involved in the induction of autophagy-related cell death by high-dose MetF in hepatocellular carcinoma (HCC). Computational alanine scanning mutagenesis revealed that MetF and VDAC1 (D9, E203) interact electrostatically. MetF disrupts the IP3R-GRP75-VDAC1 complex, which plays a key role in stabilizing mitochondria-associated ER membranes (MAMs), by binding to VDAC1. This disruption leads to increased cytosolic calcium levels, thereby contributing to autophagy induction. MetF also decreased the AMP/ATP ratio and activated the AMPK pathway. Cells with genetic knockdown of VDAC1 mimicked the activity of MetF. In conclusion, this study provides new insights into the involvement of MetF in ionic interactions with VDAC1, contributing to its anticancer effects in HCC. These findings help elucidate the diverse biological and pharmacological effects of MetF, particularly its influence on autophagy, as well as the potential of MetF as a therapeutic agent for diseases characterized by VDAC1 overexpression. Metformin, a common type 2 diabetes drug, is known for its glucose-lowering effects. The study used several cell lines and advanced techniques to investigate how Metformin induces cancer cell death. This experimental research included cell cultures and molecular analysis. They found that Metformin targets a mitochondrial protein called VDAC1. This interaction disrupts energy production and increases autophagy, leading to cancer cell death. The results showed that Metformin binds to VDAC1, reducing mitochondrial calcium and ATP levels, which activates autophagy and kills cancer cells. The researchers concluded that the ionic interaction of Metformin with VDAC1 is critical for its anticancer effects. Future studies could explore Metformin as a treatment for cancers with high VDAC1 expression. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"The anticancer effect of metformin targets VDAC1 via ER-mitochondria interactions-mediated autophagy in HCC","authors":"Minjeong Ko, Jiho Kim, Raudah Lazim, Ju Yeon Lee, Jin Young Kim, Vijayakumar Gosu, Yoonji Lee, Sun Choi, Ho Jeong Kwon","doi":"10.1038/s12276-024-01357-1","DOIUrl":"10.1038/s12276-024-01357-1","url":null,"abstract":"Metformin (MetF) is used worldwide as a first-line therapy for type 2 diabetes. Recently, interest in the pleiotropic effects of MetF, such as its anticancer and antiaging properties, has increased. However, the molecular target of MetF and the detailed mechanism underlying its ability to inhibit cell growth through autophagy induction remain incompletely understood. In this study, using an innovative label-free drug affinity responsive target stability (DARTS)-LC-MS/MS method, we discovered that mitochondrial voltage-dependent anion channel 1 (VDAC1) is a novel binding protein involved in the induction of autophagy-related cell death by high-dose MetF in hepatocellular carcinoma (HCC). Computational alanine scanning mutagenesis revealed that MetF and VDAC1 (D9, E203) interact electrostatically. MetF disrupts the IP3R-GRP75-VDAC1 complex, which plays a key role in stabilizing mitochondria-associated ER membranes (MAMs), by binding to VDAC1. This disruption leads to increased cytosolic calcium levels, thereby contributing to autophagy induction. MetF also decreased the AMP/ATP ratio and activated the AMPK pathway. Cells with genetic knockdown of VDAC1 mimicked the activity of MetF. In conclusion, this study provides new insights into the involvement of MetF in ionic interactions with VDAC1, contributing to its anticancer effects in HCC. These findings help elucidate the diverse biological and pharmacological effects of MetF, particularly its influence on autophagy, as well as the potential of MetF as a therapeutic agent for diseases characterized by VDAC1 overexpression. Metformin, a common type 2 diabetes drug, is known for its glucose-lowering effects. The study used several cell lines and advanced techniques to investigate how Metformin induces cancer cell death. This experimental research included cell cultures and molecular analysis. They found that Metformin targets a mitochondrial protein called VDAC1. This interaction disrupts energy production and increases autophagy, leading to cancer cell death. The results showed that Metformin binds to VDAC1, reducing mitochondrial calcium and ATP levels, which activates autophagy and kills cancer cells. The researchers concluded that the ionic interaction of Metformin with VDAC1 is critical for its anticancer effects. Future studies could explore Metformin as a treatment for cancers with high VDAC1 expression. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2714-2725"},"PeriodicalIF":9.5,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01357-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-02DOI: 10.1038/s12276-024-01358-0
Jun Bum Park, Min Young Lee, Jooseung Lee, Geon Ho Moon, Sung Joon Kim, Yang-Sook Chun
Cellular receptors regulate physiological responses by interacting with ligands, thus playing a crucial role in intercellular communication. Receptors are categorized on the basis of their location and engage in diverse biochemical mechanisms, which include posttranslational modifications (PTMs). Considering the broad impact and diversity of PTMs on cellular functions, we focus narrowly on neddylation, a modification closely resembling ubiquitination. We systematically organize its canonical and noncanonical roles in modulating proteins associated with cellular receptors with the goal of providing a more detailed perspective on the intricacies of both intracellular and cell-surface receptors. Proteins undergo posttranslational modifications (PTMs) to maintain physiological balance. Neddylation, a type of PTM, involves attaching a small ubiquitin-like molecule, NEDD8, to target proteins. In this study, J.B.P. and colleagues explore the role of neddylation role in cellular receptors. The researchers conducted a review to understand how neddylation affects different types of receptors, including membrane and intracellular receptors. They examined both canonical (cullin-dependent) and noncanonical pathways regulated by neddylation. The study systematically analyzes the impact of neddylation on receptor stability, signaling, and function. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Neddylation steers the fate of cellular receptors","authors":"Jun Bum Park, Min Young Lee, Jooseung Lee, Geon Ho Moon, Sung Joon Kim, Yang-Sook Chun","doi":"10.1038/s12276-024-01358-0","DOIUrl":"10.1038/s12276-024-01358-0","url":null,"abstract":"Cellular receptors regulate physiological responses by interacting with ligands, thus playing a crucial role in intercellular communication. Receptors are categorized on the basis of their location and engage in diverse biochemical mechanisms, which include posttranslational modifications (PTMs). Considering the broad impact and diversity of PTMs on cellular functions, we focus narrowly on neddylation, a modification closely resembling ubiquitination. We systematically organize its canonical and noncanonical roles in modulating proteins associated with cellular receptors with the goal of providing a more detailed perspective on the intricacies of both intracellular and cell-surface receptors. Proteins undergo posttranslational modifications (PTMs) to maintain physiological balance. Neddylation, a type of PTM, involves attaching a small ubiquitin-like molecule, NEDD8, to target proteins. In this study, J.B.P. and colleagues explore the role of neddylation role in cellular receptors. The researchers conducted a review to understand how neddylation affects different types of receptors, including membrane and intracellular receptors. They examined both canonical (cullin-dependent) and noncanonical pathways regulated by neddylation. The study systematically analyzes the impact of neddylation on receptor stability, signaling, and function. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2569-2577"},"PeriodicalIF":9.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01358-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-02DOI: 10.1038/s12276-024-01361-5
Hyejin Yeo, Ji-Hye Lim, Ji Eom, MinJeong Kim, Hyeji Kwon, Sang-Wook Kang, Youngsup Song
Characterized by UCP1 expression and abundant mitochondria, brown adipose tissue (BAT) plays a crucial role in energy balance by converting chemical energy into heat through the cost of ATP production. In this study, it was demonstrated that Trib3 is a critical determinant of BAT-mediated energy expenditure and whole-body energy homeostasis. Under 60% high-fat diet conditions, Trib3 expression in BAT was elevated. Mice deficient in Trib3 are resistant to diet-induced obesity and exhibit improved glucose homeostasis due to enhanced BAT activity. Furthermore, brown adipocyte progenitor cells (APCs) lacking Trib3 exhibited increased proliferation and promoted brown adipocyte differentiation and mitochondrial biogenesis, contributing to the increase in the maximal thermogenic capacity of BAT in Trib3-deficient mice. Mechanistically, it was discovered that Trib3 expression is upregulated by free fatty acids at the transcriptional level and synergistically upregulated by DAG-PKC at the posttranslational level. This occurs through the modulation of COP1-mediated Trib3 protein turnover. Interestingly, the level of Trib3 expression in BAT increased with age. Trib3 knockout mice were protected from aging-related weight gain and impaired glucose homeostasis. These results suggest that Trib3 acts as an obesity- and aging-associated factor that negatively regulates BAT activity and that the loss of Trib3 may provide a beneficial approach to prevent obesity and aging-associated metabolic syndrome by increasing the thermogenic capacity of BAT. The study investigates how the Trib3 gene influences energy balance and obesity. Researchers discovered that Trib3 knockout mice, which lack the Trib3 gene, are resistant to diet and aging-induced obesity. This study fills a gap in understanding Trib3’s role in brown adipose tissue, a type of fat that generates heat. Researchers conducted experiments on Trib3 KO mice to examine their resistance to obesity using methods like glucose tolerance tests, indirect calorimetry, and PET imaging to analyze the mice. Results showed that Trib3 KO mice had lower body weight and better glucose metabolism compared to control mice. They concluded that Trib3 KO mice have increased energy expenditure due to enhanced BAT activity. This suggests that targeting Trib3 could help treat obesity and related metabolic disorders. Future research could explore Trib3’s role in other tissues and its potential as a therapeutic target. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Diet-induced obesity and aging-induced upregulation of Trib3 interfere with energy homeostasis by downregulating the thermogenic capacity of BAT","authors":"Hyejin Yeo, Ji-Hye Lim, Ji Eom, MinJeong Kim, Hyeji Kwon, Sang-Wook Kang, Youngsup Song","doi":"10.1038/s12276-024-01361-5","DOIUrl":"10.1038/s12276-024-01361-5","url":null,"abstract":"Characterized by UCP1 expression and abundant mitochondria, brown adipose tissue (BAT) plays a crucial role in energy balance by converting chemical energy into heat through the cost of ATP production. In this study, it was demonstrated that Trib3 is a critical determinant of BAT-mediated energy expenditure and whole-body energy homeostasis. Under 60% high-fat diet conditions, Trib3 expression in BAT was elevated. Mice deficient in Trib3 are resistant to diet-induced obesity and exhibit improved glucose homeostasis due to enhanced BAT activity. Furthermore, brown adipocyte progenitor cells (APCs) lacking Trib3 exhibited increased proliferation and promoted brown adipocyte differentiation and mitochondrial biogenesis, contributing to the increase in the maximal thermogenic capacity of BAT in Trib3-deficient mice. Mechanistically, it was discovered that Trib3 expression is upregulated by free fatty acids at the transcriptional level and synergistically upregulated by DAG-PKC at the posttranslational level. This occurs through the modulation of COP1-mediated Trib3 protein turnover. Interestingly, the level of Trib3 expression in BAT increased with age. Trib3 knockout mice were protected from aging-related weight gain and impaired glucose homeostasis. These results suggest that Trib3 acts as an obesity- and aging-associated factor that negatively regulates BAT activity and that the loss of Trib3 may provide a beneficial approach to prevent obesity and aging-associated metabolic syndrome by increasing the thermogenic capacity of BAT. The study investigates how the Trib3 gene influences energy balance and obesity. Researchers discovered that Trib3 knockout mice, which lack the Trib3 gene, are resistant to diet and aging-induced obesity. This study fills a gap in understanding Trib3’s role in brown adipose tissue, a type of fat that generates heat. Researchers conducted experiments on Trib3 KO mice to examine their resistance to obesity using methods like glucose tolerance tests, indirect calorimetry, and PET imaging to analyze the mice. Results showed that Trib3 KO mice had lower body weight and better glucose metabolism compared to control mice. They concluded that Trib3 KO mice have increased energy expenditure due to enhanced BAT activity. This suggests that targeting Trib3 could help treat obesity and related metabolic disorders. Future research could explore Trib3’s role in other tissues and its potential as a therapeutic target. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2690-2702"},"PeriodicalIF":9.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01361-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-02DOI: 10.1038/s12276-024-01360-6
Seung Seob Son, Hee Seul Jeong, Seong-Woo Lee, Eun Soo Lee, Jeong Geon Lee, Ji-Hye Lee, Jawoon Yi, Mi Ju Park, Min Sun Choi, Donghyeong Lee, Sin Young Choi, Jiheon Ha, Jeong Suk Kang, Nam-Jun Cho, Samel Park, Hyo-Wook Gil, Choon Hee Chung, Joon Seok Park, Myung Hee Kim, Jihwan Park, Eun Young Lee
Kidney fibrosis causes irreversible structural damage in chronic kidney disease and is characterized by aberrant extracellular matrix (ECM) accumulation. Although glutamyl-prolyl-tRNA synthetase 1 (EPRS1) is a crucial enzyme involved in proline-rich protein synthesis, its role in kidney fibrosis remains unclear. The present study revealed that EPRS1 expression levels were increased in the fibrotic kidneys of patients and mice, especially in fibroblasts and proximal tubular epithelial cells, on the basis of single-cell analysis and immunostaining of fibrotic kidneys. Moreover, C57BL/6 EPRS1tm1b heterozygous knockout (Eprs1+/−) and pharmacological EPRS1 inhibition with the first-in-class EPRS1 inhibitor DWN12088 protected against kidney fibrosis and dysfunction by preventing fibroblast activation and proximal tubular injury. Interestingly, in vitro assays demonstrated that EPRS1-mediated nontranslational pathways in addition to translational pathways under transforming growth factor β-treated conditions by phosphorylating SMAD family member 3 in fibroblasts and signal transducers and activators of transcription 3 in injured proximal tubules. EPRS1 knockdown and catalytic inhibition suppressed these pathways, preventing fibroblast activation, proliferation, and subsequent collagen production. Additionally, we revealed that EPRS1 caused mitochondrial damage in proximal tubules but that this damage was attenuated by EPRS1 inhibition. Our findings suggest that the EPRS1-mediated ECM accumulation induces kidney fibrosis via fibroblast activation and mitochondrial dysfunction. Therefore, targeting EPRS1 could be a potential therapeutic target for alleviating fibrotic injury in chronic kidney disease. Kidney fibrosis, a common result of chronic kidney disease, leads to irreversible kidney dysfunction. Researchers found that the enzyme EPRS1 plays a key role in this process. Researchers discovered elevated EPRS1 levels in fibrotic kidneys of both patients and mice. The study involved patients, mice, and in vitro cells such as NRK-49F, NIH3T3, and HK-2 cells. The researchers used multiple techniques, including immunohistochemistry, western blot, electron microscopy and single-cell RNA sequencing, to identify EPRS1’s role. They found that EPRS1 promotes fibrosis by activating fibroblasts and causing mitochondrial dysfunction. Single-cell RNA sequencing and western blotting identified the pathophysiological molecular pathways. Inhibiting EPRS1 by genetic and pharmacological methods reduced kidney fibrosis and improved function, suggesting it could be a new treatment for kidney fibrosis. Future research may explore EPRS1 inhibitors as potential therapies for chronic kidney disease. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"EPRS1-mediated fibroblast activation and mitochondrial dysfunction promote kidney fibrosis","authors":"Seung Seob Son, Hee Seul Jeong, Seong-Woo Lee, Eun Soo Lee, Jeong Geon Lee, Ji-Hye Lee, Jawoon Yi, Mi Ju Park, Min Sun Choi, Donghyeong Lee, Sin Young Choi, Jiheon Ha, Jeong Suk Kang, Nam-Jun Cho, Samel Park, Hyo-Wook Gil, Choon Hee Chung, Joon Seok Park, Myung Hee Kim, Jihwan Park, Eun Young Lee","doi":"10.1038/s12276-024-01360-6","DOIUrl":"10.1038/s12276-024-01360-6","url":null,"abstract":"Kidney fibrosis causes irreversible structural damage in chronic kidney disease and is characterized by aberrant extracellular matrix (ECM) accumulation. Although glutamyl-prolyl-tRNA synthetase 1 (EPRS1) is a crucial enzyme involved in proline-rich protein synthesis, its role in kidney fibrosis remains unclear. The present study revealed that EPRS1 expression levels were increased in the fibrotic kidneys of patients and mice, especially in fibroblasts and proximal tubular epithelial cells, on the basis of single-cell analysis and immunostaining of fibrotic kidneys. Moreover, C57BL/6 EPRS1tm1b heterozygous knockout (Eprs1+/−) and pharmacological EPRS1 inhibition with the first-in-class EPRS1 inhibitor DWN12088 protected against kidney fibrosis and dysfunction by preventing fibroblast activation and proximal tubular injury. Interestingly, in vitro assays demonstrated that EPRS1-mediated nontranslational pathways in addition to translational pathways under transforming growth factor β-treated conditions by phosphorylating SMAD family member 3 in fibroblasts and signal transducers and activators of transcription 3 in injured proximal tubules. EPRS1 knockdown and catalytic inhibition suppressed these pathways, preventing fibroblast activation, proliferation, and subsequent collagen production. Additionally, we revealed that EPRS1 caused mitochondrial damage in proximal tubules but that this damage was attenuated by EPRS1 inhibition. Our findings suggest that the EPRS1-mediated ECM accumulation induces kidney fibrosis via fibroblast activation and mitochondrial dysfunction. Therefore, targeting EPRS1 could be a potential therapeutic target for alleviating fibrotic injury in chronic kidney disease. Kidney fibrosis, a common result of chronic kidney disease, leads to irreversible kidney dysfunction. Researchers found that the enzyme EPRS1 plays a key role in this process. Researchers discovered elevated EPRS1 levels in fibrotic kidneys of both patients and mice. The study involved patients, mice, and in vitro cells such as NRK-49F, NIH3T3, and HK-2 cells. The researchers used multiple techniques, including immunohistochemistry, western blot, electron microscopy and single-cell RNA sequencing, to identify EPRS1’s role. They found that EPRS1 promotes fibrosis by activating fibroblasts and causing mitochondrial dysfunction. Single-cell RNA sequencing and western blotting identified the pathophysiological molecular pathways. Inhibiting EPRS1 by genetic and pharmacological methods reduced kidney fibrosis and improved function, suggesting it could be a new treatment for kidney fibrosis. Future research may explore EPRS1 inhibitors as potential therapies for chronic kidney disease. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2673-2689"},"PeriodicalIF":9.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01360-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-02DOI: 10.1038/s12276-024-01365-1
Kibong Sung, Min-Jae Jeong, Taesik Yoo, Jung Hoon Jung, Sumin Kang, Jong-Yeon Yoo, Hyun Jin Kim, Kyunghyun Park, Jung Hyun Pyo, Hyun-Yong Lee, Noah Koo, Soo-Hee Choi, Joung-Hun Kim
Post-traumatic stress disorder (PTSD) often arises after exposure to traumatic events and is characterized by dysregulated fear responses. Although the associations of erb-b2 receptor tyrosine kinase 4 (ErbB4) with various neuropsychiatric diseases, including schizophrenia and bipolar disorder, have been widely examined, the physiological roles of ErbB4 in PTSD and fear responses remain unclear. Using Cre-dependent ErbB4 knockout (KO) mice, we observed that PTSD-like fear behaviors emerged in ErbB4-deficient mice, particularly in inhibitory neurons. Specifically, the loss of ErbB4 in somatostatin-expressing (SST+) neurons was sufficient to induce PTSD-like fear responses. We also adopted the CRISPR/Cas9 system for region-specific KO of ErbB4, which revealed that ErbB4 deletion in SST+ neurons of the lateral division of the amygdala (CeL) caused elevated anxiety and PTSD-like fear generalization. Consistent with its physiological role, ErbB4 expression was diminished in CeLSST neurons from mice that exhibited PTSD-like phenotypes. While fear On and Off cells identified in the CeL displayed distinct responses to conditioned and novel cues, as previously shown, the selectivity of those On and Off cells was compromised in SSTErbB4-/- and stressed mice, which displayed strong fear generalization. Therefore, the bimodal activity that CeL On/Off cells display is likely required for proper discrimination of fearful stimuli from ambient stimuli, which should be sustained by the presence of ErbB4. Taken together, our data substantiate the correlation between PTSD-like fear responses and ErbB4 expression in CeLSST neurons and further underscore the functional effects of ErbB4 in CeLSST neurons, supporting the bimodal responses of CeL neurons. Post-traumatic stress disorder is a mental health condition that can develop after experiencing traumatic events. Researchers tried to understand the biological basis of PTSD using animal models. The researchers investigated the role of a protein called ErbB4 in fear responses related to PTSD. They used mice to study how deleting ErbB4 in specific brain cells affects fear behavior. They focused on somatostatin(SST)-expressing neurons in a brain region called the central amygdala, which is involved in processing fear. The study involved genetic modification, behavioral tests, and in vivo recording to observe changes in fear responses. The findings showed that removing ErbB4 from SST+ neurons led to increased anxiety and generalized fear, like PTSD symptoms, with specific alteration of neuronal activity. This suggests that ErbB4 helps regulate fear responses, and its absence may contribute to PTSD-like behaviors. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"ErbB4 precludes the occurrence of PTSD-like fear responses by supporting the bimodal activity of the central amygdala","authors":"Kibong Sung, Min-Jae Jeong, Taesik Yoo, Jung Hoon Jung, Sumin Kang, Jong-Yeon Yoo, Hyun Jin Kim, Kyunghyun Park, Jung Hyun Pyo, Hyun-Yong Lee, Noah Koo, Soo-Hee Choi, Joung-Hun Kim","doi":"10.1038/s12276-024-01365-1","DOIUrl":"10.1038/s12276-024-01365-1","url":null,"abstract":"Post-traumatic stress disorder (PTSD) often arises after exposure to traumatic events and is characterized by dysregulated fear responses. Although the associations of erb-b2 receptor tyrosine kinase 4 (ErbB4) with various neuropsychiatric diseases, including schizophrenia and bipolar disorder, have been widely examined, the physiological roles of ErbB4 in PTSD and fear responses remain unclear. Using Cre-dependent ErbB4 knockout (KO) mice, we observed that PTSD-like fear behaviors emerged in ErbB4-deficient mice, particularly in inhibitory neurons. Specifically, the loss of ErbB4 in somatostatin-expressing (SST+) neurons was sufficient to induce PTSD-like fear responses. We also adopted the CRISPR/Cas9 system for region-specific KO of ErbB4, which revealed that ErbB4 deletion in SST+ neurons of the lateral division of the amygdala (CeL) caused elevated anxiety and PTSD-like fear generalization. Consistent with its physiological role, ErbB4 expression was diminished in CeLSST neurons from mice that exhibited PTSD-like phenotypes. While fear On and Off cells identified in the CeL displayed distinct responses to conditioned and novel cues, as previously shown, the selectivity of those On and Off cells was compromised in SSTErbB4-/- and stressed mice, which displayed strong fear generalization. Therefore, the bimodal activity that CeL On/Off cells display is likely required for proper discrimination of fearful stimuli from ambient stimuli, which should be sustained by the presence of ErbB4. Taken together, our data substantiate the correlation between PTSD-like fear responses and ErbB4 expression in CeLSST neurons and further underscore the functional effects of ErbB4 in CeLSST neurons, supporting the bimodal responses of CeL neurons. Post-traumatic stress disorder is a mental health condition that can develop after experiencing traumatic events. Researchers tried to understand the biological basis of PTSD using animal models. The researchers investigated the role of a protein called ErbB4 in fear responses related to PTSD. They used mice to study how deleting ErbB4 in specific brain cells affects fear behavior. They focused on somatostatin(SST)-expressing neurons in a brain region called the central amygdala, which is involved in processing fear. The study involved genetic modification, behavioral tests, and in vivo recording to observe changes in fear responses. The findings showed that removing ErbB4 from SST+ neurons led to increased anxiety and generalized fear, like PTSD symptoms, with specific alteration of neuronal activity. This suggests that ErbB4 helps regulate fear responses, and its absence may contribute to PTSD-like behaviors. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2703-2713"},"PeriodicalIF":9.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01365-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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