Optineurin/OPTN is an adapter protein that plays a crucial role in mediating many cellular functions, including autophagy, vesicle trafficking, and various signalling pathways. Mutations of OPTN are linked with neurodegenerative disorders, glaucoma, and amyotrophic lateral sclerosis (ALS). Recent work has shown that OPTN provides cytoprotection from many types of stress, including oxidative stress, endoplasmic reticulum stress, protein homeostasis stress, tumour necrosis factor α, and microbial infection. Here, we discuss the mechanisms involved in cytoprotective functions of OPTN, which possibly depend on its ability to modulate various stress-induced signalling pathways. ALS- and glaucoma-causing mutants of OPTN are altered in this regulation, which may affect cell survival, particularly under various stress conditions. We suggest that OPTN deficiency created by mutations may cooperate with stress-induced signalling to enhance or cause neurodegeneration. Other functions of OPTN, such as neurotrophin secretion and vesicle trafficking, may also contribute to cytoprotection.
{"title":"Molecular aspects of cytoprotection by Optineurin during stress and disease","authors":"Ghanshyam Swarup , Swetha Medchalmi , Gopalakrishna Ramachandran , Zuberwasim Sayyad","doi":"10.1016/j.bbamcr.2024.119895","DOIUrl":"10.1016/j.bbamcr.2024.119895","url":null,"abstract":"<div><div>Optineurin/OPTN is an adapter protein that plays a crucial role in mediating many cellular functions, including autophagy, vesicle trafficking, and various signalling pathways. Mutations of OPTN are linked with neurodegenerative disorders, glaucoma, and amyotrophic lateral sclerosis (ALS). Recent work has shown that OPTN provides cytoprotection from many types of stress, including oxidative stress, endoplasmic reticulum stress, protein homeostasis stress, tumour necrosis factor α, and microbial infection. Here, we discuss the mechanisms involved in cytoprotective functions of OPTN, which possibly depend on its ability to modulate various stress-induced signalling pathways. ALS- and glaucoma-causing mutants of OPTN are altered in this regulation, which may affect cell survival, particularly under various stress conditions. We suggest that OPTN deficiency created by mutations may cooperate with stress-induced signalling to enhance or cause neurodegeneration. Other functions of OPTN, such as neurotrophin secretion and vesicle trafficking, may also contribute to cytoprotection.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119895"},"PeriodicalIF":4.6,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-26DOI: 10.1016/j.bbamcr.2024.119881
S. Ghorbanalipoor , T. Hommel , T. Kolbe , T. Fröhlich , B. Wagner , C. Posch , M. Dahlhoff
Keratins, the intermediate filament-forming proteins of the epithelial cells, are mainly expressed in keratinocytes, preserving the structural integrity and cohesion of the epidermis. There are multiple inherited skin conditions arising from mutations in the encoding genes of specific keratins, highlighting their significance in skin health. Furthermore, the aberrant expression of keratins is evidenced in certain skin diseases, such as psoriasis, atopic dermatitis, and skin cancer. Keratin 77 (KRT77) is a type II keratin with demonstrated expression in human and mouse sweat glands' ducts. Using the CRISPR/Cas9 technique, we generated a Krt77-deficient (Krt77-KO) mouse line to reveal its obscure function in skin biology and homeostasis. KRT77 loss did not result in any fetal lethality or detrimental impact on the development of the skin and its appendages. However, we identified a substantially increased expression of KRT1 in the skin of the Krt77-KO mouse line in comparison with control littermates at both mRNA and protein levels using RT-qPCR and western blot analyses, respectively. Based on these findings, we concluded that the absence of KRT77 in the murine skin leads to upregulation of KRT1, an alternative epidermal type II keratin within the same subfamily as KRT77, which rescues the lack of KRT77.
角蛋白是上皮细胞的中间丝形成蛋白，主要在角质形成细胞中表达，可保持表皮结构的完整性和凝聚力。特定角蛋白的编码基因突变会导致多种遗传性皮肤病，这凸显了角蛋白在皮肤健康中的重要作用。此外，某些皮肤病，如牛皮癣、特应性皮炎和皮肤癌，也证明了角蛋白的异常表达。角蛋白 77（KRT77）是一种 II 型角蛋白，在人类和小鼠汗腺导管中均有表达。我们利用 CRISPR/Cas9 技术生成了 Krt77 缺失（Krt77-KO）小鼠品系，以揭示其在皮肤生物学和稳态中的模糊功能。KRT77 缺失不会导致胎儿夭折，也不会对皮肤及其附属器官的发育产生有害影响。然而，通过 RT-qPCR 和 Western 印迹分析，我们发现 Krt77-KO 小鼠品系的皮肤中 KRT1 的表达在 mRNA 和蛋白质水平上都比对照品系高得多。基于这些发现，我们得出结论：小鼠皮肤中 KRT77 的缺失会导致 KRT1 的上调，KRT1 是与 KRT77 属于同一亚家族的另一种表皮 II 型角蛋白，它能挽救 KRT77 的缺失。
{"title":"The loss of keratin 77 in murine skin is functionally compensated by keratin 1","authors":"S. Ghorbanalipoor , T. Hommel , T. Kolbe , T. Fröhlich , B. Wagner , C. Posch , M. Dahlhoff","doi":"10.1016/j.bbamcr.2024.119881","DOIUrl":"10.1016/j.bbamcr.2024.119881","url":null,"abstract":"<div><div>Keratins, the intermediate filament-forming proteins of the epithelial cells, are mainly expressed in keratinocytes, preserving the structural integrity and cohesion of the epidermis. There are multiple inherited skin conditions arising from mutations in the encoding genes of specific keratins, highlighting their significance in skin health. Furthermore, the aberrant expression of keratins is evidenced in certain skin diseases, such as psoriasis, atopic dermatitis, and skin cancer. Keratin 77 (KRT77) is a type II keratin with demonstrated expression in human and mouse sweat glands' ducts. Using the CRISPR/Cas9 technique, we generated a <em>Krt77</em>-deficient (<em>Krt77</em>-KO) mouse line to reveal its obscure function in skin biology and homeostasis. KRT77 loss did not result in any fetal lethality or detrimental impact on the development of the skin and its appendages. However, we identified a substantially increased expression of KRT1 in the skin of the <em>Krt77</em>-KO mouse line in comparison with control littermates at both mRNA and protein levels using RT-qPCR and western blot analyses, respectively. Based on these findings, we concluded that the absence of KRT77 in the murine skin leads to upregulation of KRT1, an alternative epidermal type II keratin within the same subfamily as KRT77, which rescues the lack of KRT77.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 2","pages":"Article 119881"},"PeriodicalIF":4.6,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142723916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-26DOI: 10.1016/j.bbamcr.2024.119883
Masayuki Ebina , Yuri Miura , Fumio Sakane
Diacylglycerol kinase δ (DGKδ) phosphorylates diacylglycerol and converts it into phosphatidic acid. DGKδ contributes to glucose uptake as one of its cellular functions. However, detail mechanisms underlying the regulation of DGKδ protein stability remain unelucidated. Herein, we identified ubiquitin-specific peptidase 11 (USP11) in the DGKδ protein complex by DGKδ-interactome analysis. By mapping analysis, we clarified that a wider region of USP11, including the catalytic domain 1 region, and both the C1 domains and catalytic subdomain-a of DGKδ mainly contributed to their association. Cellular dysfunction of USP11 by mitoxiantrone (a USP11-specific inhibitor) or siRNA knockdown markedly decreased DGKδ protein levels. Additionally, we found that DGKδ ubiquitination was increased by USP11 dysfunction, and cumulative ubiquitination was reduced by rescue manipulation. Functionally, USP11 dysfunction reduced cellular glucose uptake. Altogether, our findings provide the first evidence that USP11 deubiquitination-dependently stabilizes DGKδ to maintain cellular glucose uptake.
{"title":"Ubiquitin-specific peptidase 11 selectively interacts with and deubiquitination-dependently stabilizes diacylglycerol kinase δ to maintain cellular glucose uptake","authors":"Masayuki Ebina , Yuri Miura , Fumio Sakane","doi":"10.1016/j.bbamcr.2024.119883","DOIUrl":"10.1016/j.bbamcr.2024.119883","url":null,"abstract":"<div><div>Diacylglycerol kinase δ (DGKδ) phosphorylates diacylglycerol and converts it into phosphatidic acid. DGKδ contributes to glucose uptake as one of its cellular functions. However, detail mechanisms underlying the regulation of DGKδ protein stability remain unelucidated. Herein, we identified ubiquitin-specific peptidase 11 (USP11) in the DGKδ protein complex by DGKδ-interactome analysis. By mapping analysis, we clarified that a wider region of USP11, including the catalytic domain 1 region, and both the C1 domains and catalytic subdomain-a of DGKδ mainly contributed to their association. Cellular dysfunction of USP11 by mitoxiantrone (a USP11-specific inhibitor) or siRNA knockdown markedly decreased DGKδ protein levels. Additionally, we found that DGKδ ubiquitination was increased by USP11 dysfunction, and cumulative ubiquitination was reduced by rescue manipulation. Functionally, USP11 dysfunction reduced cellular glucose uptake. Altogether, our findings provide the first evidence that USP11 deubiquitination-dependently stabilizes DGKδ to maintain cellular glucose uptake.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 2","pages":"Article 119883"},"PeriodicalIF":4.6,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-25DOI: 10.1016/j.bbamcr.2024.119880
Long Chen , Menglu Zhao , Linjing Liu , Tan Wang , Xue Gong , Jun Zhang
Despite advances in understanding breast cancer (BC) molecular subtypes, the mechanisms underlying its grade of malignancy remain unclear. Our study reveals that low expression of the RNA-binding protein ELAVL1 is linked to higher-grade malignancy and poorer prognosis in malignant BC subtypes. Notably, knockdown of ELAVL1 increased the expression of key stem cell markers (CD44, SOX2, OCT4, KLF4, and NANOG) and enhanced tumorsphere formation. These findings offer new insights into BC malignancy and suggest potential improvements in prognostic assessment and treatment strategies for better patient outcomes.
{"title":"ELAVL1 governs breast cancer malignancy by regulating cell stemness","authors":"Long Chen , Menglu Zhao , Linjing Liu , Tan Wang , Xue Gong , Jun Zhang","doi":"10.1016/j.bbamcr.2024.119880","DOIUrl":"10.1016/j.bbamcr.2024.119880","url":null,"abstract":"<div><div>Despite advances in understanding breast cancer (BC) molecular subtypes, the mechanisms underlying its grade of malignancy remain unclear. Our study reveals that low expression of the RNA-binding protein ELAVL1 is linked to higher-grade malignancy and poorer prognosis in malignant BC subtypes. Notably, knockdown of ELAVL1 increased the expression of key stem cell markers (CD44, SOX2, OCT4, KLF4, and NANOG) and enhanced tumorsphere formation. These findings offer new insights into BC malignancy and suggest potential improvements in prognostic assessment and treatment strategies for better patient outcomes.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 2","pages":"Article 119880"},"PeriodicalIF":4.6,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142698202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Multidrug resistance (MDR) poses one of the primary challenges for cancer treatment, especially in cases of metastatic disease. Various mechanisms contribute to MDR, including the overexpression of ATP-binding cassette (ABC) proteins. In this context, we reviewed the literature to establish a correlation between the overexpression of ABC proteins and MDR in cancer, considering both in vitro and clinical studies. Initially, we presented an overview of the seven subfamilies of ABC proteins, along with the subcellular localization of each protein. Subsequently, we identified a panel of 20 ABC proteins (ABCA1–3, ABCA7, ABCB1–2, ABCB4–6, ABCC1–5, ABCC10–11, ABCE1, ABCF2, ABCG1, and ABCG2) associated with MDR. We also emphasize the significance of drug sequestration by certain ABC proteins into intracellular compartments. Among the anticancer drugs linked to MDR, 29 were definitively identified as substrates for at least one of the three most crucial ABC transporters: ABCB1, ABCC1, and ABCG2. We further discussed that the most commonly used drugs in standard regimens for mainly breast cancer, lung cancer, and acute lymphoblastic leukemia could be subject to MDR mediated by ABC transporters. Collectively, these insights will aid in conducting new studies aimed at a deeper understanding of the clinical MDR mediated by ABC proteins and in designing more effective pharmacological treatments to enhance the objective response rate in cancer patients.
{"title":"The association of ABC proteins with multidrug resistance in cancer","authors":"Andrezza Viviany Lourenço Marques , Bruna Estelita Ruginsk , Larissa de Oliveira Prado, Diogo Eugênio de Lima, Isabelle Watanabe Daniel, Vivian Rotuno Moure, Glaucio Valdameri","doi":"10.1016/j.bbamcr.2024.119878","DOIUrl":"10.1016/j.bbamcr.2024.119878","url":null,"abstract":"<div><div>Multidrug resistance (MDR) poses one of the primary challenges for cancer treatment, especially in cases of metastatic disease. Various mechanisms contribute to MDR, including the overexpression of ATP-binding cassette (ABC) proteins. In this context, we reviewed the literature to establish a correlation between the overexpression of ABC proteins and MDR in cancer, considering both <em>in vitro</em> and clinical studies. Initially, we presented an overview of the seven subfamilies of ABC proteins, along with the subcellular localization of each protein. Subsequently, we identified a panel of 20 ABC proteins (ABCA1–3, ABCA7, ABCB1–2, ABCB4–6, ABCC1–5, ABCC10–11, ABCE1, ABCF2, ABCG1, and ABCG2) associated with MDR. We also emphasize the significance of drug sequestration by certain ABC proteins into intracellular compartments. Among the anticancer drugs linked to MDR, 29 were definitively identified as substrates for at least one of the three most crucial ABC transporters: ABCB1, ABCC1, and ABCG2. We further discussed that the most commonly used drugs in standard regimens for mainly breast cancer, lung cancer, and acute lymphoblastic leukemia could be subject to MDR mediated by ABC transporters. Collectively, these insights will aid in conducting new studies aimed at a deeper understanding of the clinical MDR mediated by ABC proteins and in designing more effective pharmacological treatments to enhance the objective response rate in cancer patients.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 2","pages":"Article 119878"},"PeriodicalIF":4.6,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-14DOI: 10.1016/j.bbamcr.2024.119877
Dan Wang , Xinwen Bi , Le Zhao , Shijian Xiang , Wenjie Xi , Shushu Yang , Weijie Wu , Tufeng Chen , Lei Zheng , Xinjin Chi , Yang Kang
Sepsis is a heterogeneous and imprecise disorder characterized by aberrant response to infection which has been accredited for detrimental impact on immune homeostasis. Recently, macrophage metabolism has been recognized as attractive targets to develop novel immunomodulatory therapy for sepsis research. However, the fine-tuning regulators dictating macrophage functions and the specific mechanisms underlying macrophage metabolic reprogramming remain largely obscure. Sphingosine-1-phosphate (S1P), a metabolic mediator of sphingolipid catabolism, predominantly formed through sphingosine kinase 1 (SphK1) catalyzing, mediates inflammation in sepsis by binding to S1P receptor 3 (S1PR3) expressed in macrophages. Here we demonstrate that SphK1/S1PR3 axis was upregulated in lipopolysaccharide (LPS)-induced macrophages and septic mice lungs, cascading the activation of proglycolytic signaling such as HIF-1α, HK2 and PFKFB3. Targeted inhibition of Sphk1 by PF-543 effectively abrogated upregulated SphK1/S1PR3 axis in vitro and in vivo. In addition, PF-543 significantly suppressed sepsis-related inflammation and multi-organ injury in vivo. Furthermore, PF-543 not only blunted key glycolytic enzymes HIF-1α, HK2, and PFKFB3 in LPS-treated macrophages but also inhibited HK2 and PFKFB3 in septic mice. Silencing or inhibiting SphK1 tempered pro-inflammatory M1 macrophages while boosted anti-inflammatory M2 macrophages. Intriguingly, S1PR3 knockdown proficiently dampened glycolysis-associated markers, retrieved LPS-modulated M1/M2 polarization and attenuated NF-κB p65 activation. In conclusion, our study provides the first evidence that PF-543 orchestrates proportional imbalance of macrophage polarization and the Warburg effect in a SphK1/S1PR3 dependent manner during sepsis, mitigating both hyperinflammation and multi-organ failure, adding a novel puzzle piece to pharmacologically exploitable therapy for sepsis.
{"title":"Targeting SphK1/S1PR3 axis ameliorates sepsis-induced multiple organ injury via orchestration of macrophage polarization and glycolysis","authors":"Dan Wang , Xinwen Bi , Le Zhao , Shijian Xiang , Wenjie Xi , Shushu Yang , Weijie Wu , Tufeng Chen , Lei Zheng , Xinjin Chi , Yang Kang","doi":"10.1016/j.bbamcr.2024.119877","DOIUrl":"10.1016/j.bbamcr.2024.119877","url":null,"abstract":"<div><div>Sepsis is a heterogeneous and imprecise disorder characterized by aberrant response to infection which has been accredited for detrimental impact on immune homeostasis. Recently, macrophage metabolism has been recognized as attractive targets to develop novel immunomodulatory therapy for sepsis research. However, the fine-tuning regulators dictating macrophage functions and the specific mechanisms underlying macrophage metabolic reprogramming remain largely obscure. Sphingosine-1-phosphate (S1P), a metabolic mediator of sphingolipid catabolism, predominantly formed through sphingosine kinase 1 (SphK1) catalyzing, mediates inflammation in sepsis by binding to S1P receptor 3 (S1PR3) expressed in macrophages. Here we demonstrate that SphK1/S1PR3 axis was upregulated in lipopolysaccharide (LPS)-induced macrophages and septic mice lungs, cascading the activation of proglycolytic signaling such as HIF-1α, HK2 and PFKFB3. Targeted inhibition of Sphk1 by PF-543 effectively abrogated upregulated SphK1/S1PR3 axis <em>in vitro</em> and <em>in vivo</em>. In addition, PF-543 significantly suppressed sepsis-related inflammation and multi-organ injury <em>in vivo</em>. Furthermore, PF-543 not only blunted key glycolytic enzymes HIF-1α, HK2, and PFKFB3 in LPS-treated macrophages but also inhibited HK2 and PFKFB3 in septic mice. Silencing or inhibiting SphK1 tempered pro-inflammatory M1 macrophages while boosted anti-inflammatory M2 macrophages. Intriguingly, S1PR3 knockdown proficiently dampened glycolysis-associated markers, retrieved LPS-modulated M1/M2 polarization and attenuated NF-κB p65 activation. In conclusion, our study provides the first evidence that PF-543 orchestrates proportional imbalance of macrophage polarization and the Warburg effect in a SphK1/S1PR3 dependent manner during sepsis, mitigating both hyperinflammation and multi-organ failure, adding a novel puzzle piece to pharmacologically exploitable therapy for sepsis.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 1","pages":"Article 119877"},"PeriodicalIF":4.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-14DOI: 10.1016/j.bbamcr.2024.119876
Eléa A. Renaud, Ambre J.M. Maupin, Sébastien Besteiro
Iron‑sulfur cluster are ubiquitous and ancient protein cofactors that support a wide array of essential cellular functions. In eukaryotes, their assembly requires specific and dedicated machineries in each subcellular compartment. Apicomplexans are parasitic protists that are collectively responsible for a significant burden on the health of humans and other animals, and most of them harbor two organelles of endosymbiotic origin: a mitochondrion, and a plastid of high metabolic importance called the apicoplast. Consequently, apicomplexan parasites have distinct iron‑sulfur cluster assembly machineries located to their endosymbiotic organelles, as well as a cytosolic pathway. Recent findings have not only shown the importance of iron‑sulfur cluster assembly for the fitness of these parasites, but also highlighted parasite-specific features that may be promising for the development of targeted anti-parasitic strategies.
{"title":"Iron‑sulfur cluster biogenesis and function in Apicomplexa parasites","authors":"Eléa A. Renaud, Ambre J.M. Maupin, Sébastien Besteiro","doi":"10.1016/j.bbamcr.2024.119876","DOIUrl":"10.1016/j.bbamcr.2024.119876","url":null,"abstract":"<div><div>Iron‑sulfur cluster are ubiquitous and ancient protein cofactors that support a wide array of essential cellular functions. In eukaryotes, their assembly requires specific and dedicated machineries in each subcellular compartment. Apicomplexans are parasitic protists that are collectively responsible for a significant burden on the health of humans and other animals, and most of them harbor two organelles of endosymbiotic origin: a mitochondrion, and a plastid of high metabolic importance called the apicoplast. Consequently, apicomplexan parasites have distinct iron‑sulfur cluster assembly machineries located to their endosymbiotic organelles, as well as a cytosolic pathway. Recent findings have not only shown the importance of iron‑sulfur cluster assembly for the fitness of these parasites, but also highlighted parasite-specific features that may be promising for the development of targeted anti-parasitic strategies.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 1","pages":"Article 119876"},"PeriodicalIF":4.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1016/j.bbamcr.2024.119875
Khushboo Sharma , Pooja Rai , Madhu G. Tapadia
Compelling evidence has strongly linked unregulated sugar levels to developing Alzheimer's disease, suggesting Alzheimer's to be ‘diabetes of the brain or ‘type 3 diabetes. Insulin resistance contributes to the pathogenesis of Alzheimer's disease due to uncontrolled and unchecked blood glucose, though the interrelatedness between Alzheimer's disease and type 2 diabetes is debatable. Here we describe the consequences of inducing type 3 diabetes by feeding Drosophila on a high sucrose diet, which effectively mimics the pathophysiology of diabetes. A high sucrose diet increases glycogen and lipid accumulation. Inducing type 3 diabetes worsened neurodegeneration and accelerated disease progression in Drosophila expressing the Alzheimer's Familial Arctic mutation. High sucrose milieu also negatively affected locomotor ability and reduced the lifespan in the Alzheimer's disease model of Drosophila. The results showed that creating diabetic conditions by using insulin receptor (InR) knockdown in the eyes of Drosophila led to a degenerative phenotype, indicating a genetic interaction between the insulin signaling pathway and Alzheimer's disease. The expression of PERK reflects disruption in the endoplasmic reticulum homeostasis due to amyloid-β (Aβ) under a high sucrose diet. These observations demonstrated an association between type 3 diabetes and Alzheimer's disease, and that a high sucrose environment has a degenerating effect on Alzheimer's disease condition.
{"title":"Impaired insulin signaling and diet-induced type 3 diabetes pathophysiology increase amyloid β expression in the Drosophila model of Alzheimer's disease","authors":"Khushboo Sharma , Pooja Rai , Madhu G. Tapadia","doi":"10.1016/j.bbamcr.2024.119875","DOIUrl":"10.1016/j.bbamcr.2024.119875","url":null,"abstract":"<div><div>Compelling evidence has strongly linked unregulated sugar levels to developing Alzheimer's disease, suggesting Alzheimer's to be ‘diabetes of the brain or ‘type 3 diabetes. Insulin resistance contributes to the pathogenesis of Alzheimer's disease due to uncontrolled and unchecked blood glucose, though the interrelatedness between Alzheimer's disease and type 2 diabetes is debatable. Here we describe the consequences of inducing type 3 diabetes by feeding <em>Drosophila</em> on a high sucrose diet, which effectively mimics the pathophysiology of diabetes. A high sucrose diet increases glycogen and lipid accumulation. Inducing type 3 diabetes worsened neurodegeneration and accelerated disease progression in <em>Drosophila</em> expressing the Alzheimer's Familial Arctic mutation. High sucrose milieu also negatively affected locomotor ability and reduced the lifespan in the Alzheimer's disease model of <em>Drosophila</em>. The results showed that creating diabetic conditions by using insulin receptor (InR) knockdown in the eyes of <em>Drosophila</em> led to a degenerative phenotype, indicating a genetic interaction between the insulin signaling pathway and Alzheimer's disease. The expression of PERK reflects disruption in the endoplasmic reticulum homeostasis due to amyloid-β (Aβ) under a high sucrose diet. These observations demonstrated an association between type 3 diabetes and Alzheimer's disease, and that a high sucrose environment has a degenerating effect on Alzheimer's disease condition.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 1","pages":"Article 119875"},"PeriodicalIF":4.6,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1016/j.bbamcr.2024.119874
A. Falconieri
The interactions between mechanical forces and neuronal dynamics have long intrigued researchers. Several studies revealed that force plays a pivotal role in shaping axonal outgrowth. However, the molecular mechanisms underpinning force-driven axonal plasticity remain not completely elucidated. This review explores the relationship between force and axonal plasticity, with a focus on local mechanisms, including local translation and axonal transport, and the emerging concept of force-driven cross-talk, a dialogue in which local dynamics are tightly regulated. Recent experimental evidence suggests that microtubules may serve as key mediators of this cross-talk, orchestrating the coordination between local mechanisms and facilitating mass addition.
{"title":"Interplay of force and local mechanisms in axonal plasticity and beyond","authors":"A. Falconieri","doi":"10.1016/j.bbamcr.2024.119874","DOIUrl":"10.1016/j.bbamcr.2024.119874","url":null,"abstract":"<div><div>The interactions between mechanical forces and neuronal dynamics have long intrigued researchers. Several studies revealed that force plays a pivotal role in shaping axonal outgrowth. However, the molecular mechanisms underpinning force-driven axonal plasticity remain not completely elucidated. This review explores the relationship between force and axonal plasticity, with a focus on local mechanisms, including local translation and axonal transport, and the emerging concept of force-driven cross-talk, a dialogue in which local dynamics are tightly regulated. Recent experimental evidence suggests that microtubules may serve as key mediators of this cross-talk, orchestrating the coordination between local mechanisms and facilitating mass addition.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 1","pages":"Article 119874"},"PeriodicalIF":4.6,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-06DOI: 10.1016/j.bbamcr.2024.119872
Anabela Ferreira , Stéphen Manon , Akandé Rouchidane Eyitayo , Susana R. Chaves , Manuela Côrte-Real , Ana Preto , Maria João Sousa
Kirsten rat sarcoma viral oncogene homolog (KRAS) belongs to the GTPase RAS superfamily, which regulates several cell-signaling pathways involved in the control of important cellular functions, including apoptosis. Oncogenic mutations in KRAS are considered the most common gain-of-function mutations, affecting 30–50 % of colorectal cancer (CRC) patients. While RAS proteins usually play an anti-apoptotic role, little is known about the involvement of KRAS mutations in apoptosis regulation. Here, we aimed to elucidate the role of mutated human KRAS in the regulation of BAX, a key pro-apoptotic member of the Bcl-2 family. For this purpose, we took advantage of the simpler yeast model Saccharomyces cerevisiae, using cells deficient in the main yeast RAS isoform (ras2Δ) co-expressing wild-type KRAS (KRASWT) or the most frequent KRAS mutations found in CRC - KRASG12D, KRASG12V or KRASG13D, along with human BAX. We show that, in comparison with KRASWT, KRAS mutants confer resistance to BAX-induced death and cytochrome c (cyt c) release. The modulation of BAX by KRAS isoforms seems to result from a direct interaction between these proteins, as they co-localize at the mitochondria and there is evidence they may physically interact. We further show that acetic acid significantly increased cell death in cells expressing BAX and co-expressing oncogenic KRAS mutants, but not KRASWT. This suggests a potential mechanism explaining the increased sensitivity of CRC cells harboring a KRAS-activated pathway to acetate. These findings contribute to a clearer understanding of how KRAS regulate BAX function, a relevant aspect in tumor progression.
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