Ferroptosis, an iron-dependent form of programmed cell death characterized by excessive lipid hydroperoxides accumulation, emerges as a promising target in cancer therapy. Among the solute carrier (SLC) superfamily, the cystine/glutamate transporter system antiporter components SLC3A2 and SLC7A11 are known to regulate ferroptosis by facilitating cystine import for ferroptosis inhibition. However, the contribution of additional SLC superfamily members to ferroptosis remains poorly understood. Here, we use a targeted CRISPR-Cas9 screen of the SLC superfamily to identify SLC25A1 as a critical ferroptosis regulator in human cancer cells. SLC25A1 drives citrate export from the mitochondria to the cytosol, where it fuels acetyl-CoA synthesis by ATP citrate lyase (ACLY). This acetyl-CoA supply sustains FSP1 acetylation and prevents its degradation by the proteasome via K29-linked ubiquitin chains. K168 is the primary site of FSP1 acetylation and deacetylation by KAT2B and HDAC3, respectively. Pharmacological inhibition of SLC25A1 and ACLY significantly enhances cancer cell susceptibility to ferroptosis both in vitro and in vivo. Targeting the SLC25A1-ACLY axis is therefore a potential therapeutic strategy for ferroptosis-targeted cancer intervention.
{"title":"SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ferroptosis susceptibility via FSP1 acetylation.","authors":"Wei Li,Jing Han,Bin Huang,Tengteng Xu,Yihong Wan,Dan Luo,Weiyao Kong,Ying Yu,Lei Zhang,Yong Nian,Bo Chu,Chengqian Yin","doi":"10.1038/s44318-025-00369-5","DOIUrl":"https://doi.org/10.1038/s44318-025-00369-5","url":null,"abstract":"Ferroptosis, an iron-dependent form of programmed cell death characterized by excessive lipid hydroperoxides accumulation, emerges as a promising target in cancer therapy. Among the solute carrier (SLC) superfamily, the cystine/glutamate transporter system antiporter components SLC3A2 and SLC7A11 are known to regulate ferroptosis by facilitating cystine import for ferroptosis inhibition. However, the contribution of additional SLC superfamily members to ferroptosis remains poorly understood. Here, we use a targeted CRISPR-Cas9 screen of the SLC superfamily to identify SLC25A1 as a critical ferroptosis regulator in human cancer cells. SLC25A1 drives citrate export from the mitochondria to the cytosol, where it fuels acetyl-CoA synthesis by ATP citrate lyase (ACLY). This acetyl-CoA supply sustains FSP1 acetylation and prevents its degradation by the proteasome via K29-linked ubiquitin chains. K168 is the primary site of FSP1 acetylation and deacetylation by KAT2B and HDAC3, respectively. Pharmacological inhibition of SLC25A1 and ACLY significantly enhances cancer cell susceptibility to ferroptosis both in vitro and in vivo. Targeting the SLC25A1-ACLY axis is therefore a potential therapeutic strategy for ferroptosis-targeted cancer intervention.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-28DOI: 10.1038/s44318-024-00359-z
Yan Huang,Hua Lu,Yao Liu,Jiabei Wang,Qingan Xia,Xiangmin Shi,Yan Jin,Xiaolin Liang,Wei Wang,Xiaopeng Ma,Yangyi Wang,Meng Gong,Canjun Li,Chunlei Cang,Qinghua Cui,Ceshi Chen,Tao Shen,Lianxin Liu,Xiangting Wang
mTOR plays a pivotal role in cancer growth control upon amino acid response. Recently, CDK inhibitor P27KIP1 has been reported as a noncanonical inhibitor of mTOR signaling in MEFs, via unclear mechanisms. Here, we find that P27KIP1 degradation via E3 ligase TRIM21 is inhibited by human micropeptide hSPAR through its C-terminus (hSPAR-C), causing P27KIP1's cytoplasmic accumulation in breast cancer cells. Furthermore, hSPAR/hSPAR-C also serves as an inhibitor of glutamine transporter SLC38A2 expression and thereby decreases the cellular glutamine levels specifically in cancer cells. The resultant glutamine deprivation sequentially triggers translocation of cytoplasmic P27KIP1 to lysosomes, where P27KIP1 disrupts the Ragulator complex and suppresses mTORC1 assembly. Administration of hSPAR or hSPAR-C significantly impedes breast cancer cell proliferation and tumor growth in xenograft models. These findings define hSPAR as an intrinsic control factor for cellular glutamine levels and as a novel tumor suppressor inhibiting mTORC1 assembly.
{"title":"Micropeptide hSPAR regulates glutamine levels and suppresses mammary tumor growth via a TRIM21-P27KIP1-mTOR axis.","authors":"Yan Huang,Hua Lu,Yao Liu,Jiabei Wang,Qingan Xia,Xiangmin Shi,Yan Jin,Xiaolin Liang,Wei Wang,Xiaopeng Ma,Yangyi Wang,Meng Gong,Canjun Li,Chunlei Cang,Qinghua Cui,Ceshi Chen,Tao Shen,Lianxin Liu,Xiangting Wang","doi":"10.1038/s44318-024-00359-z","DOIUrl":"https://doi.org/10.1038/s44318-024-00359-z","url":null,"abstract":"mTOR plays a pivotal role in cancer growth control upon amino acid response. Recently, CDK inhibitor P27KIP1 has been reported as a noncanonical inhibitor of mTOR signaling in MEFs, via unclear mechanisms. Here, we find that P27KIP1 degradation via E3 ligase TRIM21 is inhibited by human micropeptide hSPAR through its C-terminus (hSPAR-C), causing P27KIP1's cytoplasmic accumulation in breast cancer cells. Furthermore, hSPAR/hSPAR-C also serves as an inhibitor of glutamine transporter SLC38A2 expression and thereby decreases the cellular glutamine levels specifically in cancer cells. The resultant glutamine deprivation sequentially triggers translocation of cytoplasmic P27KIP1 to lysosomes, where P27KIP1 disrupts the Ragulator complex and suppresses mTORC1 assembly. Administration of hSPAR or hSPAR-C significantly impedes breast cancer cell proliferation and tumor growth in xenograft models. These findings define hSPAR as an intrinsic control factor for cellular glutamine levels and as a novel tumor suppressor inhibiting mTORC1 assembly.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-28DOI: 10.1038/s44318-025-00368-6
Yongxiang Zhao,Pietro Vidossich,Biff Forbush,Junfeng Ma,Jesse Rinehart,Marco De Vivo,Erhu Cao
Na+-K+-Cl- cotransporters functions as an anion importers, regulating trans-epithelial chloride secretion, cell volume, and renal salt reabsorption. Loop diuretics, including furosemide, bumetanide, and torsemide, antagonize both NKCC1 and NKCC2, and are first-line medicines for the treatment of edema and hypertension. NKCC1 activation by the molecular crowding sensing WNK kinases is critical if cells are to combat shrinkage during hypertonic stress; however, how phosphorylation accelerates NKCC1 ion transport remains unclear. Here, we present co-structures of phospho-activated NKCC1 bound with furosemide, bumetanide, or torsemide showing that furosemide and bumetanide utilize a carboxyl group to coordinate and co-occlude a K+, whereas torsemide encroaches and expels the K+ from the site. We also found that an amino-terminal segment of NKCC1, once phosphorylated, interacts with the carboxyl-terminal domain, and together, they engage with intracellular ion exit and appear to be poised to facilitate rapid ion translocation. Together, these findings enhance our understanding of NKCC-mediated epithelial ion transport and the molecular mechanisms of its inhibition by loop diuretics.
{"title":"Structural basis for human NKCC1 inhibition by loop diuretic drugs.","authors":"Yongxiang Zhao,Pietro Vidossich,Biff Forbush,Junfeng Ma,Jesse Rinehart,Marco De Vivo,Erhu Cao","doi":"10.1038/s44318-025-00368-6","DOIUrl":"https://doi.org/10.1038/s44318-025-00368-6","url":null,"abstract":"Na+-K+-Cl- cotransporters functions as an anion importers, regulating trans-epithelial chloride secretion, cell volume, and renal salt reabsorption. Loop diuretics, including furosemide, bumetanide, and torsemide, antagonize both NKCC1 and NKCC2, and are first-line medicines for the treatment of edema and hypertension. NKCC1 activation by the molecular crowding sensing WNK kinases is critical if cells are to combat shrinkage during hypertonic stress; however, how phosphorylation accelerates NKCC1 ion transport remains unclear. Here, we present co-structures of phospho-activated NKCC1 bound with furosemide, bumetanide, or torsemide showing that furosemide and bumetanide utilize a carboxyl group to coordinate and co-occlude a K+, whereas torsemide encroaches and expels the K+ from the site. We also found that an amino-terminal segment of NKCC1, once phosphorylated, interacts with the carboxyl-terminal domain, and together, they engage with intracellular ion exit and appear to be poised to facilitate rapid ion translocation. Together, these findings enhance our understanding of NKCC-mediated epithelial ion transport and the molecular mechanisms of its inhibition by loop diuretics.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Metabolic requirements of dividing hepatocytes are prerequisite for liver regeneration after injury. In contrast to transcriptional dynamics during liver repair, its metabolic dependencies remain poorly defined. Here, we screened metabolic genes differentially regulated during liver regeneration, and report that SLC13A2, a transporter for TCA cycle intermediates, is decreased in rapid response to partial hepatectomy in mice and recovered along restoration of liver mass and function. Liver-specific overexpression or depletion of SLC13A2 promoted or attenuated liver regeneration, respectively. SLC13A2 increased cleavage of SREBP2, and expression of cholesterol metabolism genes, including LDLR and HMGCR. Mechanistically, SLC13A2 promotes import of citrate into hepatocytes, serving as building block for ACLY-dependent acetyl-CoA formation and de novo synthesis of cholesterol. In line, the pre-administration of the HMGCR inhibitor lovastatin abolished SLC13A2-mediated liver regeneration. Similarly, ACLY inhibition suppressed SLC13A2-promoted cholesterol synthesis for hepatocellular proliferation and liver regeneration in vivo. In sum, this study demonstrates that citrate transported by SLC13A2 acts as an intermediate metabolite to restore the metabolic homeostasis during liver regeneration, suggesting SLC13A2 as a potential drug target after liver damage.
{"title":"SLC13A2 promotes hepatocyte metabolic remodeling and liver regeneration by enhancing de novo cholesterol biosynthesis.","authors":"Li Shi,Hao Chen,Yuxin Zhang,Donghao An,Mengyao Qin,Wanting Yu,Bin Wen,Dandan He,Haiping Hao,Jing Xiong","doi":"10.1038/s44318-025-00362-y","DOIUrl":"https://doi.org/10.1038/s44318-025-00362-y","url":null,"abstract":"Metabolic requirements of dividing hepatocytes are prerequisite for liver regeneration after injury. In contrast to transcriptional dynamics during liver repair, its metabolic dependencies remain poorly defined. Here, we screened metabolic genes differentially regulated during liver regeneration, and report that SLC13A2, a transporter for TCA cycle intermediates, is decreased in rapid response to partial hepatectomy in mice and recovered along restoration of liver mass and function. Liver-specific overexpression or depletion of SLC13A2 promoted or attenuated liver regeneration, respectively. SLC13A2 increased cleavage of SREBP2, and expression of cholesterol metabolism genes, including LDLR and HMGCR. Mechanistically, SLC13A2 promotes import of citrate into hepatocytes, serving as building block for ACLY-dependent acetyl-CoA formation and de novo synthesis of cholesterol. In line, the pre-administration of the HMGCR inhibitor lovastatin abolished SLC13A2-mediated liver regeneration. Similarly, ACLY inhibition suppressed SLC13A2-promoted cholesterol synthesis for hepatocellular proliferation and liver regeneration in vivo. In sum, this study demonstrates that citrate transported by SLC13A2 acts as an intermediate metabolite to restore the metabolic homeostasis during liver regeneration, suggesting SLC13A2 as a potential drug target after liver damage.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-15DOI: 10.1038/s44318-024-00343-7
Kazumi Shimaoka,Kei Hori,Satoshi Miyashita,Yukiko U Inoue,Nao K N Tabe,Asami Sakamoto,Ikuko Hasegawa,Kayo Nishitani,Kunihiko Yamashiro,Saki F Egusa,Shoji Tatsumoto,Yasuhiro Go,Manabu Abe,Kenji Sakimura,Takayoshi Inoue,Takuya Imamura,Mikio Hoshino
AUTS2 syndrome is characterized by intellectual disability and microcephaly, and is often associated with autism spectrum disorder, but the underlying mechanisms, particularly concerning microcephaly, remain incompletely understood. Here, we analyze mice mutated for the transcriptional regulator AUTS2, which recapitulate microcephaly. Their brains exhibit reduced division of intermediate progenitor cells (IPCs), leading to fewer neurons and decreased thickness in the upper-layer cortex. Increased expression of the AUTS2 transcriptional target Robo1 in the mutant animals suppresses IPC division, and transcriptomic and chromatin profiling shows that AUTS2 primarily represses transcription of genes like Robo1 in IPCs. Regions around the transcriptional start sites of AUTS2 target genes are enriched for the repressive histone modification H3K27me3, which is reduced in Auts2 mutants. Furthermore, we find that AUTS2 interacts with Polycomb complex PRC2, with which it cooperates to promote IPC division. These findings shed light on the microcephaly phenotype observed in the AUTS2 syndrome.
{"title":"The microcephaly-associated transcriptional regulator AUTS2 cooperates with Polycomb complex PRC2 to produce upper-layer neurons in mice.","authors":"Kazumi Shimaoka,Kei Hori,Satoshi Miyashita,Yukiko U Inoue,Nao K N Tabe,Asami Sakamoto,Ikuko Hasegawa,Kayo Nishitani,Kunihiko Yamashiro,Saki F Egusa,Shoji Tatsumoto,Yasuhiro Go,Manabu Abe,Kenji Sakimura,Takayoshi Inoue,Takuya Imamura,Mikio Hoshino","doi":"10.1038/s44318-024-00343-7","DOIUrl":"https://doi.org/10.1038/s44318-024-00343-7","url":null,"abstract":"AUTS2 syndrome is characterized by intellectual disability and microcephaly, and is often associated with autism spectrum disorder, but the underlying mechanisms, particularly concerning microcephaly, remain incompletely understood. Here, we analyze mice mutated for the transcriptional regulator AUTS2, which recapitulate microcephaly. Their brains exhibit reduced division of intermediate progenitor cells (IPCs), leading to fewer neurons and decreased thickness in the upper-layer cortex. Increased expression of the AUTS2 transcriptional target Robo1 in the mutant animals suppresses IPC division, and transcriptomic and chromatin profiling shows that AUTS2 primarily represses transcription of genes like Robo1 in IPCs. Regions around the transcriptional start sites of AUTS2 target genes are enriched for the repressive histone modification H3K27me3, which is reduced in Auts2 mutants. Furthermore, we find that AUTS2 interacts with Polycomb complex PRC2, with which it cooperates to promote IPC division. These findings shed light on the microcephaly phenotype observed in the AUTS2 syndrome.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"119 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Autophagy mediates the degradation of harmful material within lysosomes. In aggrephagy, the pathway mediating the degradation of aggregated, ubiquitinated proteins, this cargo material is collected in larger condensates prior to its sequestration by autophagosomes. In this process, the autophagic cargo receptors SQSTM1/p62 and NBR1 drive cargo condensation, while TAX1BP1, which binds to NBR1, recruits the autophagy machinery to facilitate autophagosome biogenesis at the condensates. The mechanistic basis for the TAX1BP1-mediated switch from cargo collection to its sequestration is unclear. Here we show that TAX1BP1 is not a constitutive component of the condensates. Its recruitment correlates with the induction of autophagosome biogenesis. TAX1BP1 is sufficient to recruit the TBK1 kinase via the SINTBAD adapter. We define the NBR1-TAX1BP1-binding site, which is adjacent to the GABARAP/LC3 interaction site, and demonstrate that the recruitment of TAX1BP1 to cargo mimetics can be enhanced by an increased ubiquitin load. Our study suggests that autophagosome biogenesis is initiated once sufficient cargo is collected in the condensates.
{"title":"Recruitment of autophagy initiator TAX1BP1 advances aggrephagy from cargo collection to sequestration.","authors":"Bernd Bauer,Jonas Idinger,Martina Schuschnig,Luca Ferrari,Sascha Martens","doi":"10.1038/s44318-024-00280-5","DOIUrl":"https://doi.org/10.1038/s44318-024-00280-5","url":null,"abstract":"Autophagy mediates the degradation of harmful material within lysosomes. In aggrephagy, the pathway mediating the degradation of aggregated, ubiquitinated proteins, this cargo material is collected in larger condensates prior to its sequestration by autophagosomes. In this process, the autophagic cargo receptors SQSTM1/p62 and NBR1 drive cargo condensation, while TAX1BP1, which binds to NBR1, recruits the autophagy machinery to facilitate autophagosome biogenesis at the condensates. The mechanistic basis for the TAX1BP1-mediated switch from cargo collection to its sequestration is unclear. Here we show that TAX1BP1 is not a constitutive component of the condensates. Its recruitment correlates with the induction of autophagosome biogenesis. TAX1BP1 is sufficient to recruit the TBK1 kinase via the SINTBAD adapter. We define the NBR1-TAX1BP1-binding site, which is adjacent to the GABARAP/LC3 interaction site, and demonstrate that the recruitment of TAX1BP1 to cargo mimetics can be enhanced by an increased ubiquitin load. Our study suggests that autophagosome biogenesis is initiated once sufficient cargo is collected in the condensates.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Senescent cells play a causative role in many diseases, and their elimination is a promising therapeutic strategy. Here, through a genome-wide CRISPR/Cas9 screen, we identify the gene PPIF, encoding the mitochondrial protein cyclophilin D (CypD), as a novel senolytic target. Cyclophilin D promotes the transient opening of the mitochondrial permeability transition pore (mPTP), which serves as a failsafe mechanism for calcium efflux. We show that senescent cells exhibit a high frequency of transient CypD/mPTP opening events, known as 'flickering'. Inhibition of CypD using genetic or pharmacologic tools, including cyclosporin A, leads to the toxic accumulation of mitochondrial Ca2+ and the death of senescent cells. Genetic or pharmacological inhibition of NCLX, another mitochondrial calcium efflux channel, also leads to senolysis, while inhibition of the main Ca2+ influx channel, MCU, prevents senolysis induced by CypD inhibition. We conclude that senescent cells are highly vulnerable to elevated mitochondrial Ca2+ ions, and that transient CypD/mPTP opening is a critical adaptation mechanism for the survival of senescent cells.
{"title":"Cyclophilin D plays a critical role in the survival of senescent cells.","authors":"Margherita Protasoni,Vanessa López-Polo,Camille Stephan-Otto Attolini,Julian Brandariz,Nicolas Herranz,Joaquin Mateo,Sergio Ruiz,Oscar Fernandez-Capetillo,Marta Kovatcheva,Manuel Serrano","doi":"10.1038/s44318-024-00259-2","DOIUrl":"https://doi.org/10.1038/s44318-024-00259-2","url":null,"abstract":"Senescent cells play a causative role in many diseases, and their elimination is a promising therapeutic strategy. Here, through a genome-wide CRISPR/Cas9 screen, we identify the gene PPIF, encoding the mitochondrial protein cyclophilin D (CypD), as a novel senolytic target. Cyclophilin D promotes the transient opening of the mitochondrial permeability transition pore (mPTP), which serves as a failsafe mechanism for calcium efflux. We show that senescent cells exhibit a high frequency of transient CypD/mPTP opening events, known as 'flickering'. Inhibition of CypD using genetic or pharmacologic tools, including cyclosporin A, leads to the toxic accumulation of mitochondrial Ca2+ and the death of senescent cells. Genetic or pharmacological inhibition of NCLX, another mitochondrial calcium efflux channel, also leads to senolysis, while inhibition of the main Ca2+ influx channel, MCU, prevents senolysis induced by CypD inhibition. We conclude that senescent cells are highly vulnerable to elevated mitochondrial Ca2+ ions, and that transient CypD/mPTP opening is a critical adaptation mechanism for the survival of senescent cells.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24DOI: 10.1038/s44318-024-00278-z
Shuting Ding,Shuxian Feng,Shibo Zhou,Zhengran Zhao,Xiao Liang,Jiao Wang,Ruishuang Fu,Rui Deng,Tao Zhang,Shujun Shao,Jingquan Yu,Christine H Foyer,Kai Shi
Plants face constant threats from pathogens, leading to growth retardation and crop failure. Cell-surface leucine-rich repeat receptor-like kinases (LRR-RLKs) are crucial for plant growth and defense, but their specific functions, especially to necrotrophic fungal pathogens, are largely unknown. Here, we identified an LRR-RLK (Solyc06g069650) in tomato (Solanum lycopersicum) induced by the economically important necrotrophic pathogen Botrytis cinerea. Knocking out this LRR-RLK reduced plant growth and increased sensitivity to B. cinerea, while its overexpression led to enhanced growth, yield, and resistance. We named this LRR-RLK as BRAK (B. cinerea resistance-associated kinase). Yeast two-hybrid screen revealed BRAK interacted with phytosulfokine (PSK) receptor PSKR1. PSK-induced growth and defense responses were impaired in pskr1, brak single and double mutants, as well as in PSKR1-overexpressing plants with silenced BRAK. Moreover, BRAK and PSKR1 phosphorylated each other, promoting their interaction as detected by microscale thermophoresis. This reciprocal phosphorylation was crucial for growth and resistance. In summary, we identified BRAK as a novel regulator of seedling growth, fruit yield and defense, offering new possibilities for developing fungal disease-tolerant plants without compromising yield.
{"title":"A novel LRR receptor-like kinase BRAK reciprocally phosphorylates PSKR1 to enhance growth and defense in tomato.","authors":"Shuting Ding,Shuxian Feng,Shibo Zhou,Zhengran Zhao,Xiao Liang,Jiao Wang,Ruishuang Fu,Rui Deng,Tao Zhang,Shujun Shao,Jingquan Yu,Christine H Foyer,Kai Shi","doi":"10.1038/s44318-024-00278-z","DOIUrl":"https://doi.org/10.1038/s44318-024-00278-z","url":null,"abstract":"Plants face constant threats from pathogens, leading to growth retardation and crop failure. Cell-surface leucine-rich repeat receptor-like kinases (LRR-RLKs) are crucial for plant growth and defense, but their specific functions, especially to necrotrophic fungal pathogens, are largely unknown. Here, we identified an LRR-RLK (Solyc06g069650) in tomato (Solanum lycopersicum) induced by the economically important necrotrophic pathogen Botrytis cinerea. Knocking out this LRR-RLK reduced plant growth and increased sensitivity to B. cinerea, while its overexpression led to enhanced growth, yield, and resistance. We named this LRR-RLK as BRAK (B. cinerea resistance-associated kinase). Yeast two-hybrid screen revealed BRAK interacted with phytosulfokine (PSK) receptor PSKR1. PSK-induced growth and defense responses were impaired in pskr1, brak single and double mutants, as well as in PSKR1-overexpressing plants with silenced BRAK. Moreover, BRAK and PSKR1 phosphorylated each other, promoting their interaction as detected by microscale thermophoresis. This reciprocal phosphorylation was crucial for growth and resistance. In summary, we identified BRAK as a novel regulator of seedling growth, fruit yield and defense, offering new possibilities for developing fungal disease-tolerant plants without compromising yield.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The identification of host factors with antiviral potential is important for developing effective prevention and therapeutic strategies against SARS-CoV-2 infection. Here, by using immortalized cell lines, intestinal organoids, ex vivo intestinal tissues and humanized ACE2 mouse model as proof-of-principle systems, we have identified lipolysis-stimulated lipoprotein receptor (LSR) as a crucial host defense factor against SARS-CoV-2 infection in the small intestine. Loss of endogenous LSR enhances ACE2-dependent infection by SARS-CoV-2 Spike (S) protein-pseudotyped virus and authentic SARS-CoV-2 virus, and exogenous administration of LSR protects against viral infection. Mechanistically, LSR interacts with ACE2 both in cis and in trans, preventing its binding to S protein, and thus inhibiting viral entry and S protein-mediated cell-cell fusion. Finally, a small LSR-derived peptide blocks S protein binding to the ACE2 receptor in vitro. These results identify both a previously unknown function for LSR in antiviral host defense against SARS-CoV-2, with potential implications for peptide-based pan-variant therapeutic interventions.
确定具有抗病毒潜能的宿主因子对于制定有效的预防和治疗策略来对抗 SARS-CoV-2 感染非常重要。在这里，我们利用永生化细胞系、肠道器官组织、体外肠道组织和人源化 ACE2 小鼠模型作为原理验证系统，鉴定出脂肪分解刺激脂蛋白受体（LSR）是小肠中抵抗 SARS-CoV-2 感染的关键宿主防御因子。内源性 LSR 的缺失会增强 SARS-CoV-2 Spike (S) 蛋白伪型病毒和真 SARS-CoV-2 病毒对 ACE2 的依赖性感染，而外源性给予 LSR 则可防止病毒感染。从机理上讲，LSR 与 ACE2 存在顺式和反式相互作用，阻止其与 S 蛋白结合，从而抑制病毒进入和 S 蛋白介导的细胞-细胞融合。最后，LSR 衍生的一种小肽在体外阻断了 S 蛋白与 ACE2 受体的结合。这些结果确定了 LSR 在抗 SARS-CoV-2 病毒宿主防御中的一种以前未知的功能，对基于肽的泛变异治疗干预具有潜在的意义。
{"title":"Tight junction protein LSR is a host defense factor against SARS-CoV-2 infection in the small intestine.","authors":"Yanan An,Chao Wang,Ziqi Wang,Feng Kong,Hao Liu,Min Jiang,Ti Liu,Shu Zhang,Kaige Du,Liang Yin,Peng Jiao,Ying Li,Baozhen Fan,Chengjun Zhou,Mingxia Wang,Hui Sun,Jie Lei,Shengtian Zhao,Yongfeng Gong","doi":"10.1038/s44318-024-00281-4","DOIUrl":"https://doi.org/10.1038/s44318-024-00281-4","url":null,"abstract":"The identification of host factors with antiviral potential is important for developing effective prevention and therapeutic strategies against SARS-CoV-2 infection. Here, by using immortalized cell lines, intestinal organoids, ex vivo intestinal tissues and humanized ACE2 mouse model as proof-of-principle systems, we have identified lipolysis-stimulated lipoprotein receptor (LSR) as a crucial host defense factor against SARS-CoV-2 infection in the small intestine. Loss of endogenous LSR enhances ACE2-dependent infection by SARS-CoV-2 Spike (S) protein-pseudotyped virus and authentic SARS-CoV-2 virus, and exogenous administration of LSR protects against viral infection. Mechanistically, LSR interacts with ACE2 both in cis and in trans, preventing its binding to S protein, and thus inhibiting viral entry and S protein-mediated cell-cell fusion. Finally, a small LSR-derived peptide blocks S protein binding to the ACE2 receptor in vitro. These results identify both a previously unknown function for LSR in antiviral host defense against SARS-CoV-2, with potential implications for peptide-based pan-variant therapeutic interventions.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"44 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maintaining mitochondrial homeostasis is crucial for cell survival and organismal health, as evidenced by the links between mitochondrial dysfunction and various diseases, including Alzheimer's disease (AD). Here, we report that lncMtDloop, a non-coding RNA of unknown function encoded within the D-loop region of the mitochondrial genome, maintains mitochondrial RNA levels and function with age. lncMtDloop expression is decreased in the brains of both human AD patients and 3xTg AD mouse models. Furthermore, lncMtDloop binds to mitochondrial transcription factor A (TFAM), facilitates TFAM recruitment to mtDNA promoters, and increases mitochondrial transcription. To allow lncMtDloop transport into mitochondria via the PNPASE-dependent trafficking pathway, we fused the 3'UTR localization sequence of mitochondrial ribosomal protein S12 (MRPS12) to its terminal end, generating a specified stem-loop structure. Introducing this allotropic lncMtDloop into AD model mice significantly improved mitochondrial function and morphology, and ameliorated AD-like pathology and behavioral deficits of AD model mice. Taken together, these data provide insights into lncMtDloop as a regulator of mitochondrial transcription and its contribution to Alzheimer's pathogenesis.
{"title":"The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer's disease.","authors":"Wandi Xiong,Kaiyu Xu,Jacquelyne Ka-Li Sun,Siling Liu,Baizhen Zhao,Jie Shi,Karl Herrup,Hei-Man Chow,Lin Lu,Jiali Li","doi":"10.1038/s44318-024-00270-7","DOIUrl":"https://doi.org/10.1038/s44318-024-00270-7","url":null,"abstract":"Maintaining mitochondrial homeostasis is crucial for cell survival and organismal health, as evidenced by the links between mitochondrial dysfunction and various diseases, including Alzheimer's disease (AD). Here, we report that lncMtDloop, a non-coding RNA of unknown function encoded within the D-loop region of the mitochondrial genome, maintains mitochondrial RNA levels and function with age. lncMtDloop expression is decreased in the brains of both human AD patients and 3xTg AD mouse models. Furthermore, lncMtDloop binds to mitochondrial transcription factor A (TFAM), facilitates TFAM recruitment to mtDNA promoters, and increases mitochondrial transcription. To allow lncMtDloop transport into mitochondria via the PNPASE-dependent trafficking pathway, we fused the 3'UTR localization sequence of mitochondrial ribosomal protein S12 (MRPS12) to its terminal end, generating a specified stem-loop structure. Introducing this allotropic lncMtDloop into AD model mice significantly improved mitochondrial function and morphology, and ameliorated AD-like pathology and behavioral deficits of AD model mice. Taken together, these data provide insights into lncMtDloop as a regulator of mitochondrial transcription and its contribution to Alzheimer's pathogenesis.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"233 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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