Life Science Alliance最新文献

Message from the new Executive Editor. 来自新任执行编辑的信息。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-04-22 Print Date: 2025-05-01 DOI: 10.26508/lsa.202503362

Tim Fessenden

引用次数: 0

Lipid-driven Src self-association modulates its transformation capacity. 脂质驱动的Src自关联调节其转化能力。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-03-13 Print Date: 2025-05-01 DOI: 10.26508/lsa.202403019

Irrem-Laareb Mohammad, Marina I Giannotti, Elise Fourgous, Yvan Boublik, Alejandro Fernández, Anabel-Lise Le Roux, Audrey Sirvent, Marta Taulés, Serge Roche, Miquel Pons

{"title":"Lipid-driven Src self-association modulates its transformation capacity.","authors":"Irrem-Laareb Mohammad, Marina I Giannotti, Elise Fourgous, Yvan Boublik, Alejandro Fernández, Anabel-Lise Le Roux, Audrey Sirvent, Marta Taulés, Serge Roche, Miquel Pons","doi":"10.26508/lsa.202403019","DOIUrl":"10.26508/lsa.202403019","url":null,"abstract":"Src tyrosine kinase regulates cell growth and adhesion through membrane signaling, and its deregulation is associated with cancer. Although active Src is anchored to the plasma membrane, the role of membrane lipids in its regulation remains unclear. Here, we report that Src self-associates via a lysine cluster in its SH4 region, a process mediated by lipids in human cells and in vitro. Mutation of the lysine cluster to arginine alters Src self-association and modulates its transforming function in human cells. Lipid-anchored micron-sized condensates of full-length Src form in supported homogeneous lipid bilayers (i.e., independently of lipid phase separation). Condensates also arise from the purified Src N-terminal regulatory element, which includes the myristoylated SH4 domain, the intrinsically disordered Unique domain, and the globular SH3 domain. However, the isolated SH4 domain alone forms small protein-lipid clusters rather than micron-sized condensates. Our findings reveal lipid-mediated kinase self-association as an additional regulatory mechanism for Src. This mechanism may also apply to other membrane-associated signaling proteins containing similar lysine clusters in their unstructured regions.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11909415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625408","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}

引用次数: 0

The late-onset Alzheimer's disease risk factor RHBDF2 is a modifier of microglial TREM2 proteolysis. 晚发性阿尔茨海默病风险因子 RHBDF2 是小胶质细胞 TREM2 蛋白溶解的调节因子。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-03-13 Print Date: 2025-05-01 DOI: 10.26508/lsa.202403080

Georg Jocher, Gozde Ozcelik, Stephan A Müller, Hung-En Hsia, Miranda Lastra Osua, Laura I Hofmann, Marlene Aßfalg, Lina Dinkel, Xiao Feng, Kai Schlepckow, Michael Willem, Christian Haass, Sabina Tahirovic, Carl P Blobel, Stefan F Lichtenthaler

{"title":"The late-onset Alzheimer's disease risk factor RHBDF2 is a modifier of microglial TREM2 proteolysis.","authors":"Georg Jocher, Gozde Ozcelik, Stephan A Müller, Hung-En Hsia, Miranda Lastra Osua, Laura I Hofmann, Marlene Aßfalg, Lina Dinkel, Xiao Feng, Kai Schlepckow, Michael Willem, Christian Haass, Sabina Tahirovic, Carl P Blobel, Stefan F Lichtenthaler","doi":"10.26508/lsa.202403080","DOIUrl":"10.26508/lsa.202403080","url":null,"abstract":"The cell surface receptor TREM2 is a key genetic risk factor and drug target in Alzheimer's disease (AD). In the brain, TREM2 is expressed in microglia, where it undergoes proteolytic cleavage, linked to AD risk, but the responsible protease in microglia is still unknown. Another microglial-expressed AD risk factor is catalytically inactive rhomboid 2 (iRhom2, RHBDF2), which binds to and acts as a non-catalytic subunit of the metalloprotease ADAM17. A potential role in TREM2 proteolysis is not yet known. Using microglial-like BV2 cells, bone marrow-derived macrophages, and primary murine microglia, we identify iRhom2 as a modifier of ADAM17-mediated TREM2 shedding. Loss of iRhom2 increased TREM2 in cell lysates and at the cell surface and enhanced TREM2 signaling and microglial phagocytosis of the amyloid β-peptide (Aβ). This study establishes ADAM17 as a physiological TREM2 protease in microglia and suggests iRhom2 as a potential drug target for modulating TREM2 proteolysis in AD.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11909414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624692","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}

引用次数: 0

Mechanical forces and ligand binding modulate Pseudomonas aeruginosa PilY1 mechanosensitive protein. 机械力和配体结合调节铜绿假单胞菌PilY1机械敏感蛋白。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-03-07 Print Date: 2025-05-01 DOI: 10.26508/lsa.202403111

Francisco J Cao-Garcia, Jane E Walker, Stephanie Board, Alvaro Alonso-Caballero

{"title":"Mechanical forces and ligand binding modulate Pseudomonas aeruginosa PilY1 mechanosensitive protein.","authors":"Francisco J Cao-Garcia, Jane E Walker, Stephanie Board, Alvaro Alonso-Caballero","doi":"10.26508/lsa.202403111","DOIUrl":"10.26508/lsa.202403111","url":null,"abstract":"Surface sensing initiates bacterial colonization of substrates. The protein PilY1 plays key roles during this process-surface detection, host adhesion, and motility-while experiencing mechanical perturbations of varying magnitudes. In Pseudomonas aeruginosa, the adhesion and motility functions of PilY1 are associated with integrin and calcium ligand-binding sites; however, how mechanical forces influence PilY1's dynamics and its interactions with these ligands remain unknown. Here, using single-molecule magnetic tweezers, we reveal that PilY1 is a mechanosensor protein that exhibits different behaviors depending on the force load. At high forces (>20 pN), PilY1 unfolds through a hierarchical sequence of intermediates, whose mechanical stability increases with calcium binding. This enhanced stability may help counteract type IV pilus retraction forces during motility. At low forces (<7 pN), we identify the dynamics of the integrin-binding domain, which is reminiscent of the behavior of mechanosensor proteins. Integrin binding induces a force-dependent conformational change in this domain, shortening its unfolded extension. Our findings suggest that PilY1 roles are force- and ligand-modulated, which could entail a mechanical-based compartmentalization of its functions.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11891296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586176","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}

引用次数: 0

MDC1 mediates Pellino recruitment to sites of DNA double-strand breaks. MDC1介导Pellino招募到DNA双链断裂位点。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-03-06 Print Date: 2025-05-01 DOI: 10.26508/lsa.202403074

Mònica Torres Esteban, Matthew J Stewart, Eilis Bragginton, Alice Meroni, Annica Pellizzari, Alain Jeanrenaud, Stephen J Smerdon, Manuel Stucki

{"title":"MDC1 mediates Pellino recruitment to sites of DNA double-strand breaks.","authors":"Mònica Torres Esteban, Matthew J Stewart, Eilis Bragginton, Alice Meroni, Annica Pellizzari, Alain Jeanrenaud, Stephen J Smerdon, Manuel Stucki","doi":"10.26508/lsa.202403074","DOIUrl":"10.26508/lsa.202403074","url":null,"abstract":"Ubiquitylation is critically implicated in the recognition and repair of DNA double-strand breaks. The adaptor protein MDC1 mediates the recruitment of the key DNA damage responsive E3 ubiquitin ligase RNF8 to the break sites. It does so by directly interacting with RNF8 in a phosphorylation-dependent manner that involves the RNF8 FHA domain, thus initiating targeted chromatin ubiquitylation at the break sites. Here, we report that MDC1 also directly binds to two additional E3 ubiquitin ligases, Pellino 1 and 2, which were recently implicated in the DNA damage response. Through a combination of biochemical, biophysical and X-ray crystallographic approaches, we reveal the molecular details of the MDC1-Pellino complexes. Furthermore, we show that in mammalian cells, MDC1 mediates Pellino recruitment to sites of DNA double-strand breaks by a direct phosphorylation-dependent interaction between the two proteins. Taken together, our findings provide new molecular insights into the ubiquitylation pathways that govern genome stability maintenance.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11884936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573462","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}

引用次数: 0

Reversible and effective cell cycle synchronization method for studying stage-specific processes. 可逆和有效的细胞周期同步方法研究阶段特异性过程。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-03-04 Print Date: 2025-05-01 DOI: 10.26508/lsa.202403000

Yu-Lin Chen, Syon Reddy, Aussie Suzuki

引用次数: 0

An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation. GCN2不依赖于isr的作用可防止过度的核糖体生物发生和mRNA翻译。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-03-03 Print Date: 2025-05-01 DOI: 10.26508/lsa.202403014

Mónica Román-Trufero, Istvan T Kleijn, Kevin Blighe, Jinglin Zhou, Paula Saavedra-García, Abigail Gaffar, Marilena Christoforou, Axel Bellotti, Joel Abrahams, Abdelmadjid Atrih, Douglas Lamont, Marek Gierlinski, Pooja Jayaprakash, Audrey M Michel, Eric O Aboagye, Mariia Yuneva, Glenn R Masson, Vahid Shahrezaei, Holger W Auner

{"title":"An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation.","authors":"Mónica Román-Trufero, Istvan T Kleijn, Kevin Blighe, Jinglin Zhou, Paula Saavedra-García, Abigail Gaffar, Marilena Christoforou, Axel Bellotti, Joel Abrahams, Abdelmadjid Atrih, Douglas Lamont, Marek Gierlinski, Pooja Jayaprakash, Audrey M Michel, Eric O Aboagye, Mariia Yuneva, Glenn R Masson, Vahid Shahrezaei, Holger W Auner","doi":"10.26508/lsa.202403014","DOIUrl":"10.26508/lsa.202403014","url":null,"abstract":"The integrated stress response (ISR) is a corrective physiological programme to restore cellular homeostasis that is based on the attenuation of global protein synthesis and a resource-enhancing transcriptional programme. GCN2 is the oldest of four kinases that are activated by diverse cellular stresses to trigger the ISR and acts as the primary responder to amino acid shortage and ribosome collisions. Here, using a broad multi-omics approach, we uncover an ISR-independent role of GCN2. GCN2 inhibition or depletion in the absence of discernible stress causes excessive protein synthesis and ribosome biogenesis, perturbs the cellular translatome, and results in a dynamic and broad loss of metabolic homeostasis. Cancer cells that rely on GCN2 to keep protein synthesis in check under conditions of full nutrient availability depend on GCN2 for survival and unrestricted tumour growth. Our observations describe an ISR-independent role of GCN2 in regulating the cellular proteome and translatome and suggest new avenues for cancer therapies based on unleashing excessive mRNA translation.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542476","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}

引用次数: 0

Metabolic dysregulation contributes to the development of dysferlinopathy. 代谢失调有助于异常蛋白病的发展。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-02-28 Print Date: 2025-05-01 DOI: 10.26508/lsa.202402991

Regula Furrer, Sedat Dilbaz, Stefan A Steurer, Gesa Santos, Bettina Karrer-Cardel, Danilo Ritz, Michael Sinnreich, Christoph Handschin

{"title":"Metabolic dysregulation contributes to the development of dysferlinopathy.","authors":"Regula Furrer, Sedat Dilbaz, Stefan A Steurer, Gesa Santos, Bettina Karrer-Cardel, Danilo Ritz, Michael Sinnreich, Christoph Handschin","doi":"10.26508/lsa.202402991","DOIUrl":"10.26508/lsa.202402991","url":null,"abstract":"Dysferlin is a transmembrane protein that plays a prominent role in membrane repair of damaged muscle fibers. Accordingly, mutations in the dysferlin gene cause progressive muscular dystrophies, collectively referred to as dysferlinopathies for which no effective treatment exists. Unexpectedly, experimental approaches that successfully restore membrane repair fail to prevent a dystrophic phenotype, suggesting that additional, hitherto unknown dysferlin-dependent functions contribute to the development of the pathology. Our experiments revealed an altered metabolic phenotype in dysferlin-deficient muscles, characterized by (1) mitochondrial abnormalities and elevated death signaling and (2) increased glucose uptake, reduced glycolytic protein levels, and pronounced glycogen accumulation. Strikingly, elevating mitochondrial volume density and muscle glycogen accelerates disease progression; whereas, improvement of mitochondrial function and recruitment of muscle glycogen with exercise ameliorated functional parameters in a mouse model of dysferlinopathy. Collectively, our results not only shed light on a metabolic function of dysferlin but also imply new therapeutic avenues aimed at promoting mitochondrial function and normalizing muscle glycogen to ameliorate dysferlinopathies, complementing efforts that target membrane repair.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531715","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}

引用次数: 0

Axonal transport of CHMP2b is regulated by kinesin-binding protein and disrupted by CHMP2b^intron5. CHMP2b的轴突转运受驱动蛋白结合蛋白调控，并被CHMP2bintron5破坏。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-02-28 Print Date: 2025-05-01 DOI: 10.26508/lsa.202402934

Konner R Kirwan, Veria Puerta-Alvarado, Clarissa L Waites

{"title":"Axonal transport of CHMP2b is regulated by kinesin-binding protein and disrupted by CHMP2bintron5.","authors":"Konner R Kirwan, Veria Puerta-Alvarado, Clarissa L Waites","doi":"10.26508/lsa.202402934","DOIUrl":"10.26508/lsa.202402934","url":null,"abstract":"CHMP2b is a core component of the ESCRT pathway that catalyzes formation of multivesicular bodies for endolysosomal protein degradation. Although mutation/loss-of-function of CHMP2b promotes presynaptic dysfunction and degeneration, indicating its critical role in presynaptic protein homeostasis, the mechanisms responsible for CHMP2b localization and recruitment to synapses remain unclear. Here, we characterize CHMP2b axonal trafficking and show that its transport and recruitment to presynaptic boutons, as well as its cotransport with other ESCRT proteins, are regulated by neuronal activity. In contrast, the frontotemporal dementia-causative CHMP2bintron5 mutation exhibits little processive movement or presynaptic localization in the presence or absence of neuronal activity. Instead, CHMP2bintron5 transport vesicles exhibit oscillatory behavior reminiscent of a tug-of-war between kinesin and dynein motor proteins. We show that this phenotype is caused by deficient binding of CHMP2bintron5 to kinesin-binding protein, which we identify as a key regulator of CHMP2b transport. These findings shed light on the mechanisms of CHMP2b axonal trafficking and synaptic localization, and their disruption by CHMP2bintron5.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531734","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}

引用次数: 0

Unraveling ADHD: genes, co-occurring traits, and developmental dynamics. 揭示多动症：基因，共同发生的特征，和发展动态。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-02-25 Print Date: 2025-05-01 DOI: 10.26508/lsa.202403029

Catriona J Miller, Evgeniia Golovina, Sreemol Gokuladhas, Joerg S Wicker, Jessie C Jacobsen, Justin M O'Sullivan

{"title":"Unraveling ADHD: genes, co-occurring traits, and developmental dynamics.","authors":"Catriona J Miller, Evgeniia Golovina, Sreemol Gokuladhas, Joerg S Wicker, Jessie C Jacobsen, Justin M O'Sullivan","doi":"10.26508/lsa.202403029","DOIUrl":"10.26508/lsa.202403029","url":null,"abstract":"Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental condition with a high prevalence of co-occurring conditions, contributing to increased difficulty in long-term management. Genome-wide association studies have identified variants shared between ADHD and co-occurring psychiatric disorders; however, the genetic mechanisms are not fully understood. We integrated gene expression and spatial organization data into a two-sample Mendelian randomization study for putatively causal ADHD genes in fetal and adult cortical tissues. We identified four genes putatively causal for ADHD in cortical tissues (fetal: ST3GAL3, PTPRF, PIDD1; adult: ST3GAL3, TIE1). Protein-protein interaction databases seeded with the causal ADHD genes identified biological pathways linking these genes with conditions (e.g., rheumatoid arthritis) and biomarkers (e.g., lymphocyte counts) known to be associated with ADHD, but without previously shown genetic relationships. The analysis was repeated on adult liver tissue, where putatively causal ADHD gene ST3GAL3 was linked to cholesterol traits. This analysis provides insight into the tissue-dependent temporal relationships between ADHD, co-occurring traits, and biomarkers. Importantly, it delivers evidence for the genetic interplay between co-occurring conditions, both previously studied and unstudied, with ADHD.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11861640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143501899","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}

引用次数: 0