Life Science Alliance最新文献

Dysregulated SASS6 expression promotes increased ciliogenesis and cell invasion phenotypes. 失调的SASS6表达促进纤毛发生和细胞侵袭表型的增加。

IF 2.9 2区生物学

Life Science Alliance Pub Date : 2025-08-18 Print Date: 2025-10-01 DOI: 10.26508/lsa.202402820

Eleanor Hargreaves, Rebecca Collinson, Andrew D Jenks, Adina Staszewski, Athanasios Tsalikis, Raquel Bodoque, Mar Arias-Garcia, Yasmin Abdi, Abdulaziz Al-Malki, Yinyin Yuan, Rachael Natrajan, Syed Haider, Thomas Iskratsch, Won-Jing Wang, Susana Godinho, Nicolaos J Palaskas, Fernando Calvo, Igor Vivanco, Tobias Zech, Barbara E Tanos

{"title":"Dysregulated SASS6 expression promotes increased ciliogenesis and cell invasion phenotypes.","authors":"Eleanor Hargreaves, Rebecca Collinson, Andrew D Jenks, Adina Staszewski, Athanasios Tsalikis, Raquel Bodoque, Mar Arias-Garcia, Yasmin Abdi, Abdulaziz Al-Malki, Yinyin Yuan, Rachael Natrajan, Syed Haider, Thomas Iskratsch, Won-Jing Wang, Susana Godinho, Nicolaos J Palaskas, Fernando Calvo, Igor Vivanco, Tobias Zech, Barbara E Tanos","doi":"10.26508/lsa.202402820","DOIUrl":"10.26508/lsa.202402820","url":null,"abstract":"Centriole and/or cilium defects are characteristic of cancer cells and have been linked to cancer cell invasion. However, the mechanistic bases of this regulation remain incompletely understood. Spindle assembly abnormal protein 6 homolog (SAS-6) is essential for centriole biogenesis and cilium formation. SAS-6 levels decrease at the end of mitosis and G1, resulting from APCCdh1-targeted degradation. To examine the biological consequences of unrestrained SAS-6 expression, we used a nondegradable SAS-6 mutant (SAS-6ND). This led to an increase in ciliation and cell invasion and caused an up-regulation of the YAP/TAZ pathway. SAS-6ND expression resulted in cell morphology changes, nuclear deformation, and YAP translocation to the nucleus, resulting in increased TEAD-dependent transcription. SAS-6-mediated invasion was prevented by YAP down-regulation or by blocking ciliogenesis. Similarly, down-regulation of SAS-6 in DMS273, a highly invasive and highly ciliated lung cancer cell line that overexpresses SAS-6, completely blocked cell invasion and depleted YAP protein levels. Thus, our data provide evidence for a defined role of SAS-6 in cell invasion through the activation of the YAP/TAZ pathway.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 10","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873889","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

AURKA controls oocyte spindle assembly checkpoint and chromosome alignment by HEC1 phosphorylation. AURKA通过HEC1磷酸化控制卵母细胞纺锤体组装检查点和染色体排列。

IF 2.9 2区生物学

Life Science Alliance Pub Date : 2025-05-06 Print Date: 2025-07-01 DOI: 10.26508/lsa.202403146

Cecilia S Blengini, Shuang Tang, Robert J Mendola, G John Garrisi, Jason E Swain, Karen Schindler

{"title":"AURKA controls oocyte spindle assembly checkpoint and chromosome alignment by HEC1 phosphorylation.","authors":"Cecilia S Blengini, Shuang Tang, Robert J Mendola, G John Garrisi, Jason E Swain, Karen Schindler","doi":"10.26508/lsa.202403146","DOIUrl":"10.26508/lsa.202403146","url":null,"abstract":"In human oocytes, meiosis I is error-prone, causing early miscarriages and developmental disorders. The Aurora protein kinases are key regulators of chromosome segregation in mitosis and meiosis, and their dysfunction is associated with aneuploidy. Oocytes express three Aurora kinase (AURK) proteins, but only AURKA is necessary and sufficient to support oocyte meiosis in mice. However, the unique molecular contributions to ensuring high egg quality of AURKA remain unclear. Here, using a combination of genetic and pharmacological approaches, we evaluated how AURKA phosphorylation regulates outer kinetochore function during oocyte meiosis. We found that the outer kinetochore protein Ndc80/HEC1 is constitutively phosphorylated at multiple residues by Aurora kinases during meiosis I, but that serine 69 is specifically phosphorylated by AURKA in mouse and human oocytes. We further show that serine 69 phosphorylation contributes to spindle assembly checkpoint activation and chromosome alignment during meiosis I. These results provide a fundamental mechanistic understanding of how AURKA regulates meiosis and kinetochore function to ensure meiosis I fidelity.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 7","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12056248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971263","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

DNA methylation predicts infection risk in kidney transplant recipients. DNA甲基化预测肾移植受者感染风险。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-05-05 Print Date: 2025-07-01 DOI: 10.26508/lsa.202403124

Fei-Man Hsu, Harry Pickering, Liudmilla Rubbi, Michael Thompson, Elaine F Reed, Matteo Pellegrini, Joanna M Schaenman

{"title":"DNA methylation predicts infection risk in kidney transplant recipients.","authors":"Fei-Man Hsu, Harry Pickering, Liudmilla Rubbi, Michael Thompson, Elaine F Reed, Matteo Pellegrini, Joanna M Schaenman","doi":"10.26508/lsa.202403124","DOIUrl":"10.26508/lsa.202403124","url":null,"abstract":"Kidney transplantation (KTx) is the method of choice for treating kidney failure. Identifying biomarkers predictive of transplant (Tx) outcomes is critical to optimize KTx; however, the immunosuppressive therapies required after KTx must also be considered. We applied targeted bisulfite sequencing (TBS-seq) to PBMCs isolated from 90 patients, with samples collected pre- and post-Tx (day 90), to measure DNA methylation changes. Our findings indicate that the PBMC DNA methylome is significantly affected by induction immunosuppression with anti-thymocyte globulin (ATG). We discovered that the risk of infection can be predicted using DNA methylation profiles, but not gene expression profiles. Specifically, 515 CpG loci associated with 275 genes were significantly impacted by ATG induction, even after accounting for age, sex, and cell-type composition. Notably, ATG-associated hyper-methylation down-regulates genes critical for immune response. In conclusion, this clinical omics study reveals that the immunosuppressant ATG profoundly impacts the DNA methylome of KTx recipients and identifies biomarkers that could be used in pre-Tx screening of patients vulnerable to infection, thereby informing immunosuppression strategies post-Tx.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12053434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000750","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

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

The MFN2 Q367H variant reveals a novel pathomechanism connected to mtDNA-mediated inflammation. MFN2 Q367H变异揭示了与mtdna介导的炎症相关的一种新的病理机制。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-04-02 Print Date: 2025-06-01 DOI: 10.26508/lsa.202402921

Mashiat Zaman, Govinda Sharma, Walaa Almutawa, Tyler Gb Soule, Rasha Sabouny, Matt Joel, Armaan Mohan, Cole Chute, Jeffrey T Joseph, Gerald Pfeffer, Timothy E Shutt

{"title":"The MFN2 Q367H variant reveals a novel pathomechanism connected to mtDNA-mediated inflammation.","authors":"Mashiat Zaman, Govinda Sharma, Walaa Almutawa, Tyler Gb Soule, Rasha Sabouny, Matt Joel, Armaan Mohan, Cole Chute, Jeffrey T Joseph, Gerald Pfeffer, Timothy E Shutt","doi":"10.26508/lsa.202402921","DOIUrl":"10.26508/lsa.202402921","url":null,"abstract":"Pathogenic variants in the mitochondrial protein MFN2 are typically associated with a peripheral neuropathy phenotype, but can also cause a variety of additional pathologies including myopathy. Here, we identified an uncharacterized MFN2 variant, Q367H, in a patient diagnosed with late-onset distal myopathy, but without peripheral neuropathy. Supporting the hypothesis that this variant contributes to the patient's pathology, patient fibroblasts and transdifferentiated myoblasts showed changes consistent with impairment of several MFN2 functions. We also observed mtDNA outside of the mitochondrial network that colocalized with early endosomes, and measured activation of both TLR9 and cGAS-STING inflammation pathways that sense mtDNA. Re-expressing the Q367H variant in MFN2 KO cells also induced mtDNA release, demonstrating this phenotype is a direct result of the variant. As elevated inflammation can cause myopathy, our findings linking the Q367H MFN2 variant with elevated TLR9 and cGAS-STING signalling can explain the patient's myopathy. Thus, we characterize a novel MFN2 variant in a patient with an atypical presentation that separates peripheral neuropathy and myopathy phenotypes, and establish a potential pathomechanism connecting MFN2 dysfunction to mtDNA-mediated inflammation.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772687","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

Antibodies targeting ADAM17 reverse neurite outgrowth inhibition by myelin-associated inhibitors. 针对ADAM17的抗体逆转髓鞘相关抑制剂对神经突生长的抑制。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-03-25 Print Date: 2025-06-01 DOI: 10.26508/lsa.202403126

Nayanendu Saha, Eric Chan, Rachelle P Mendoza, Yevgeniy Romin, Murray J Tipping, Dimitar B Nikolov

引用次数: 0

Divergent Plasmodium kinases drive MTOC, kinetochore and axoneme organisation in male gametogenesis. 在雄性配子体发生中，不同的疟原虫激酶驱动MTOC、着丝点和轴体组织。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-03-24 Print Date: 2025-06-01 DOI: 10.26508/lsa.202403056

Ryuji Yanase, Mohammad Zeeshan, David Jp Ferguson, Robert Markus, Declan Brady, Andrew R Bottrill, Anthony A Holder, David S Guttery, Rita Tewari

{"title":"Divergent Plasmodium kinases drive MTOC, kinetochore and axoneme organisation in male gametogenesis.","authors":"Ryuji Yanase, Mohammad Zeeshan, David Jp Ferguson, Robert Markus, Declan Brady, Andrew R Bottrill, Anthony A Holder, David S Guttery, Rita Tewari","doi":"10.26508/lsa.202403056","DOIUrl":"10.26508/lsa.202403056","url":null,"abstract":"Sexual development and male gamete formation of the malaria parasite in the mosquito midgut are initiated by rapid endomitosis in the activated male gametocyte. This process is highly regulated by protein phosphorylation, specifically by three divergent male-specific protein kinases (PKs): CDPK4, SRPK1, and MAP2. Here, we localise each PK during male gamete formation using live-cell imaging, identify their putative interacting partners by immunoprecipitation, and determine the morphological consequences of their absence using ultrastructure expansion and transmission electron microscopy. Each PK has a distinct location in either the nuclear or the cytoplasmic compartment. Protein interaction studies revealed that CDPK4 and MAP2 interact with key drivers of rapid DNA replication, whereas SRPK1 is involved in RNA translation. The absence of each PK results in severe defects in either microtubule-organising centre organisation, kinetochore segregation, or axoneme formation. This study reveals the crucial role of these PKs during endomitosis in formation of the flagellated male gamete and uncovers some of their interacting partners that may drive this process.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11933671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700750","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

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