Life Science Alliance最新文献_第2页

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

Identification of TNFAIP2 as a unique cellular regulator of CSF-1 receptor activation. 鉴定TNFAIP2作为CSF-1受体活化的独特细胞调节剂。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-02-12 Print Date: 2025-05-01 DOI: 10.26508/lsa.202403032

Randa A Abdelnaser, Masateru Hiyoshi, Naofumi Takahashi, Youssef M Eltalkhawy, Hidenobu Mizuno, Shunsuke Kimura, Koji Hase, Hiroshi Ohno, Kazuaki Monde, Akira Ono, Shinya Suzu

{"title":"Identification of TNFAIP2 as a unique cellular regulator of CSF-1 receptor activation.","authors":"Randa A Abdelnaser, Masateru Hiyoshi, Naofumi Takahashi, Youssef M Eltalkhawy, Hidenobu Mizuno, Shunsuke Kimura, Koji Hase, Hiroshi Ohno, Kazuaki Monde, Akira Ono, Shinya Suzu","doi":"10.26508/lsa.202403032","DOIUrl":"10.26508/lsa.202403032","url":null,"abstract":"The receptor of CSF-1 (CSF1R) encoding tyrosine kinase is essential for tissue macrophage development, and the therapeutic target for many tumors. However, it is not completely understood how CSF1R activation is regulated. Here, we identify the cellular protein TNF-α-induced protein 2 (TNFAIP2) as a unique regulator of CSF1R. CSF1R forms large aggregates in macrophages via unknown mechanisms. The inhibition or knockdown of TNFAIP2 reduced CSF1R aggregate formation and functional response of macrophages to CSF-1, which was consistent with reduced CSF1R activation after CSF-1 stimulation. When expressed in 293 cells, TNFAIP2 augmented CSF1R aggregate formation and CSF-1-induced CSF1R activation. CSF1R and TNFAIP2 bind the cellular phosphatidylinositol 4,5-bisphosphate (PIP2). The removal of the PIP2-binding motif of CSF1R or TNFAIP2, or the depletion of cellular PIP2 reduced CSF1R aggregate formation. Moreover, TNFAIP2 altered the cellular distribution of PIP2. Because CSF-1-induced dimerization of CSF1R is critical for its activation, our findings suggest that TNFAIP2 augments CSF1R aggregate formation via PIP2, which brings CSF1R monomers close to each other and enables the efficient dimerization and activation of CSF1R in response to CSF-1.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11821806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408792","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

Canonical and non-canonical PRC1 differentially contribute to regulation of neural stem cell fate. 规范和非规范PRC1对神经干细胞命运的调节有差异。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-02-11 Print Date: 2025-04-01 DOI: 10.26508/lsa.202403006

Janine Hoffmann, Theresa M Schütze, Annika Kolodziejczyk, Karolin Küster, Annekathrin Kränkel, Susanne Reinhardt, Razvan P Derihaci, Cahit Birdir, Pauline Wimberger, Haruhiko Koseki, Mareike Albert

{"title":"Canonical and non-canonical PRC1 differentially contribute to regulation of neural stem cell fate.","authors":"Janine Hoffmann, Theresa M Schütze, Annika Kolodziejczyk, Karolin Küster, Annekathrin Kränkel, Susanne Reinhardt, Razvan P Derihaci, Cahit Birdir, Pauline Wimberger, Haruhiko Koseki, Mareike Albert","doi":"10.26508/lsa.202403006","DOIUrl":"10.26508/lsa.202403006","url":null,"abstract":"Neocortex development is characterized by sequential phases of neural progenitor cell (NPC) expansion, neurogenesis, and gliogenesis. Polycomb-mediated epigenetic mechanisms are known to play important roles in regulating the lineage potential of NPCs during development. The composition of Polycomb repressive complex 1 (PRC1) is highly diverse in mammals and was hypothesized to contribute to context-specific regulation of cell fate. Here, we have performed a side-by-side comparison of the role of canonical PRC1.2/1.4 and non-canonical PRC1.3/1.5, all of which are expressed in the developing neocortex, in NSC proliferation and differentiation. We found that the deletion of Pcgf2/4 in NSCs led to a strong reduction in proliferation and to altered lineage fate, both during the neurogenic and gliogenic phase, whereas Pcgf3/5 played a minor role. Mechanistically, genes encoding stem cell and neurogenic factors were bound by PRC1 and differentially expressed upon Pcgf2/4 deletion. Thus, rather than different PRC1 subcomplexes contributing to different phases of neural development, we found that canonical PRC1 played a more significant role in NSC regulation during proliferative, neurogenic, and gliogenic phases compared with non-canonical PRC1.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11814486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399443","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

A biallelic variant in GORASP1 causes a novel Golgipathy with glycosylation and mitotic defects. GORASP1的双等位基因变异导致一种具有糖基化和有丝分裂缺陷的新型Golgipathy。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-02-11 Print Date: 2025-04-01 DOI: 10.26508/lsa.202403065

Sophie Lebon, Arnaud Bruneel, Séverine Drunat, Alexandra Albert, Zsolt Csaba, Monique Elmaleh, Alexandra Ntorkou, Yann Ténier, François Fenaille, Pierre Gressens, Sandrine Passemard, Odile Boespflug-Tanguy, Imen Dorboz, Vincent El Ghouzzi

{"title":"A biallelic variant in GORASP1 causes a novel Golgipathy with glycosylation and mitotic defects.","authors":"Sophie Lebon, Arnaud Bruneel, Séverine Drunat, Alexandra Albert, Zsolt Csaba, Monique Elmaleh, Alexandra Ntorkou, Yann Ténier, François Fenaille, Pierre Gressens, Sandrine Passemard, Odile Boespflug-Tanguy, Imen Dorboz, Vincent El Ghouzzi","doi":"10.26508/lsa.202403065","DOIUrl":"10.26508/lsa.202403065","url":null,"abstract":"GRASP65 is a Golgi-associated peripheral protein encoded by the GORASP1 gene and required for Golgi cisternal stacking in vitro. A key role of GRASP65 in the regulation of cell division has also been suggested. However, depletion of GRASP65 in mice has little effect on the Golgi structure and the gene has not been associated with any human phenotype to date. Here, we report the identification of the first human pathogenic variant of GORASP1 (c.1170_1171del; p.Asp390Glufs*18) in a patient combining a neurodevelopmental disorder with neurosensory, neuromuscular, and skeletal abnormalities. Functional analysis revealed that the variant leads to a total absence of GRASP65. The structure of the Golgi apparatus did not show fragmentation, but glycosylation anomalies such as hyposialylation were detected. Mitosis analyses revealed an excess of prometaphases and metaphases with polar chromosomes, suggesting a delay in the cell cycle. These phenotypes were recapitulated in RPE cells in which a similar mutation was introduced by CRISPR/Cas9. These results indicate that loss of GRASP65 in humans causes a novel Golgipathy associated with defects in glycosylation and mitotic progression.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11814487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399440","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

Screening of homing and tissue-penetrating peptides by microdialysis and in vivo phage display. 通过微透析和体内噬菌体展示筛选归巢肽和穿透组织肽。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-02-11 Print Date: 2025-05-01 DOI: 10.26508/lsa.202201490

Toini Pemmari, Stuart Prince, Niklas Wiss, Kuldar Kõiv, Ulrike May, Tarmo Mölder, Aleksander Sudakov, Fernanda Munoz Caro, Soili Lehtonen, Hannele Uusitalo-Järvinen, Tambet Teesalu, Tero Ah Järvinen

{"title":"Screening of homing and tissue-penetrating peptides by microdialysis and in vivo phage display.","authors":"Toini Pemmari, Stuart Prince, Niklas Wiss, Kuldar Kõiv, Ulrike May, Tarmo Mölder, Aleksander Sudakov, Fernanda Munoz Caro, Soili Lehtonen, Hannele Uusitalo-Järvinen, Tambet Teesalu, Tero Ah Järvinen","doi":"10.26508/lsa.202201490","DOIUrl":"10.26508/lsa.202201490","url":null,"abstract":"In vivo phage display is a method used for identification of organ- or disease-specific vascular homing peptides for targeted delivery of pharmaceutics. It is agnostic as to the nature and identity of the target molecules. The current in vivo biopanning lacks inbuilt mechanisms to select for peptides capable of vascular homing that would also be capable of tissue penetration to reach therapeutically relevant cells in the tissue parenchyma. Here, we combined in vivo phage display with microdialysis-based parenchymal recovery and high-throughput sequencing to select for peptides that, besides vascular homing, facilitate extravasation and tissue penetration. We first demonstrated in skin wounds that the method can selectively separate known homing peptides from those with additional tissue-penetrating ability. Screening of a naïve peptide library identifies peptides that home and extravasate to extravascular granulation tissue in vascularized and diabetic wounds and cross blood-retina barrier in retinopathy. Our work suggests that in vivo phage display combined with microdialysis can be used for the discovery of vascular homing peptides capable of extravasation and tissue penetration.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11814485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399383","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

FGF7 as an essential mediator for the onset of ankylosing enthesitis related to psoriatic dermatitis. FGF7作为与银屑病皮炎相关的强直性全身炎发病的重要介质。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-02-07 Print Date: 2025-04-01 DOI: 10.26508/lsa.202403073

Shin Ebihara, Yuji Owada, Masao Ono

引用次数: 0

PICH impacts the spindle assembly checkpoint via its DNA translocase and SUMO-interaction activities. PICH通过其DNA转位酶和sumo相互作用活动影响纺锤体组装检查点。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2025-02-07 Print Date: 2025-04-01 DOI: 10.26508/lsa.202403140

Bunu Lama, Hyewon Park, Anita Saraf, Victoria Hassebroek, Daniel Keifenheim, Tomoko Saito-Fujita, Noriko Saitoh, Vasilisa Aksenova, Alexei Arnaoutov, Mary Dasso, Duncan J Clarke, Yoshiaki Azuma

{"title":"PICH impacts the spindle assembly checkpoint via its DNA translocase and SUMO-interaction activities.","authors":"Bunu Lama, Hyewon Park, Anita Saraf, Victoria Hassebroek, Daniel Keifenheim, Tomoko Saito-Fujita, Noriko Saitoh, Vasilisa Aksenova, Alexei Arnaoutov, Mary Dasso, Duncan J Clarke, Yoshiaki Azuma","doi":"10.26508/lsa.202403140","DOIUrl":"10.26508/lsa.202403140","url":null,"abstract":"Either inhibiting or stabilizing SUMOylation in mitosis causes defects in chromosome segregation, suggesting that dynamic mitotic SUMOylation of proteins is critical to maintain integrity of the genome. Polo-like kinase 1-interacting checkpoint helicase (PICH), a mitotic chromatin remodeling enzyme, interacts with SUMOylated chromosomal proteins via three SUMO-interacting motifs (SIMs) to control their association with chromosomes. Using cell lines with conditional PICH depletion/PICH replacement, we revealed mitotic defects associated with compromised PICH functions toward SUMOylated chromosomal proteins. Defects in either remodeling activity or SIMs of PICH delayed mitotic progression caused by activation of the spindle assembly checkpoint (SAC) indicated by extended duration of Mad1 foci at centromeres. Proteomics analysis of chromosomal SUMOylated proteins whose abundance is controlled by PICH activity identified candidate proteins to explain the SAC activation phenotype. Among the identified candidates, Bub1 kinetochore abundance is increased upon loss of PICH. Our results demonstrated a novel relationship between PICH and the SAC, where PICH directly or indirectly affects Bub1 association at the kinetochore and impacts SAC activity to control mitosis.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"8 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370743","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