Journal of Cell Biology最新文献

Structural response of microtubule and actin cytoskeletons to direct intracellular load. 微管和肌动蛋白细胞骨架对细胞内直接负荷的结构反应。

IF 7.4 1区生物学

Journal of Cell Biology Pub Date : 2025-02-03 Epub Date: 2024-11-15 DOI: 10.1083/jcb.202403136

Ryota Orii, Hirokazu Tanimoto

{"title":"Structural response of microtubule and actin cytoskeletons to direct intracellular load.","authors":"Ryota Orii, Hirokazu Tanimoto","doi":"10.1083/jcb.202403136","DOIUrl":"10.1083/jcb.202403136","url":null,"abstract":"Microtubule and actin are the two major cytoskeletal polymers that form organized functional structures in the interior of eukaryotic cells. Although the structural mechanics of the cytoskeleton has been extensively studied by direct manipulations in in vitro reconstitution systems, such unambiguous characterizations inside the living cell are sparse. Here, we report a comprehensive analysis of how the microtubule and actin cytoskeletons structurally respond to direct intracellular load. Ferrofluid-based intracellular magnetic tweezers reveal rheological properties of the microtubule complex primarily determined by filamentous actin. The strain fields of the microtubule complex and actin meshwork follow the same scaling, suggesting that the two cytoskeletal systems behave as an integrated elastic body. The structural responses of single microtubules to contact and remote forces further evidence that the individual microtubules are enclosed by the elastic medium of actin. These results, directly characterizing the microtubule and actin cytoskeletons as an interacting continuum throughout the cytoplasm, serve as a cornerstone for the physical understanding of intracellular organization.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 2","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11572716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Functional genetics reveals modulators of antimicrotubule drug sensitivity. 功能遗传学揭示抗微管药物敏感性的调节因子

IF 7.4 1区生物学

Journal of Cell Biology Pub Date : 2025-02-03 Epub Date: 2024-11-21 DOI: 10.1083/jcb.202403065

Kuan-Chung Su, Elena Radul, Nolan K Maier, Mary-Jane Tsang, Claire Goul, Brittania Moodie, Océane Marescal, Heather R Keys, Iain M Cheeseman

{"title":"Functional genetics reveals modulators of antimicrotubule drug sensitivity.","authors":"Kuan-Chung Su, Elena Radul, Nolan K Maier, Mary-Jane Tsang, Claire Goul, Brittania Moodie, Océane Marescal, Heather R Keys, Iain M Cheeseman","doi":"10.1083/jcb.202403065","DOIUrl":"https://doi.org/10.1083/jcb.202403065","url":null,"abstract":"Microtubules play essential roles in diverse cellular processes and are important pharmacological targets for treating human disease. Here, we sought to identify cellular factors that modulate the sensitivity of cells to antimicrotubule drugs. We conducted a genome-wide CRISPR/Cas9-based functional genetics screen in human cells treated with the microtubule-destabilizing drug nocodazole or the microtubule-stabilizing drug paclitaxel. We further conducted a focused secondary screen to test drug sensitivity for ∼1,400 gene targets across two distinct human cell lines and to additionally test sensitivity to the KIF11 inhibitor, STLC. These screens defined gene targets whose loss enhances or suppresses sensitivity to antimicrotubule drugs. In addition to gene targets whose loss sensitized cells to multiple compounds, we observed cases of differential sensitivity to specific compounds and differing requirements between cell lines. Our downstream molecular analysis further revealed additional roles for established microtubule-associated proteins and identified new players in microtubule function.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 2","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Epidermal maintenance of Langerhans cells relies on autophagy-regulated lipid metabolism. 朗格汉斯细胞的表皮维持依赖于自噬调节的脂质代谢。

IF 7.4 1区生物学

Journal of Cell Biology Pub Date : 2025-02-03 Epub Date: 2024-11-13 DOI: 10.1083/jcb.202403178

Florent Arbogast, Raquel Sal-Carro, Wacym Boufenghour, Quentin Frenger, Delphine Bouis, Louise Filippi De La Palavesa, Jean-Daniel Fauny, Olivier Griso, Hélène Puccio, Rebecca Fima, Thierry Huby, Emmanuel L Gautier, Anne Molitor, Raphaël Carapito, Seiamak Bahram, Nikolaus Romani, Björn E Clausen, Benjamin Voisin, Christopher G Mueller, Frédéric Gros, Vincent Flacher

{"title":"Epidermal maintenance of Langerhans cells relies on autophagy-regulated lipid metabolism.","authors":"Florent Arbogast, Raquel Sal-Carro, Wacym Boufenghour, Quentin Frenger, Delphine Bouis, Louise Filippi De La Palavesa, Jean-Daniel Fauny, Olivier Griso, Hélène Puccio, Rebecca Fima, Thierry Huby, Emmanuel L Gautier, Anne Molitor, Raphaël Carapito, Seiamak Bahram, Nikolaus Romani, Björn E Clausen, Benjamin Voisin, Christopher G Mueller, Frédéric Gros, Vincent Flacher","doi":"10.1083/jcb.202403178","DOIUrl":"10.1083/jcb.202403178","url":null,"abstract":"Macroautophagy (often-named autophagy), a catabolic process involving autophagy-related (Atg) genes, prevents the accumulation of harmful cytoplasmic components and mobilizes energy reserves in long-lived and self-renewing cells. Autophagy deficiency affects antigen presentation in conventional dendritic cells (DCs) without impacting their survival. However, previous studies did not address epidermal Langerhans cells (LCs). Here, we demonstrate that deletion of either Atg5 or Atg7 in LCs leads to their gradual depletion. ATG5-deficient LCs showed metabolic dysregulation and accumulated neutral lipids. Despite increased mitochondrial respiratory capacity, they were unable to process lipids, eventually leading them to ferroptosis. Finally, metabolically impaired LCs upregulated proinflammatory transcripts and showed decreased expression of neuronal interaction receptors. Altogether, autophagy represents a critical regulator of lipid storage and metabolism in LCs, allowing their maintenance in the epidermis.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 2","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Securin regulates the spatiotemporal dynamics of separase. Securin 可调节分离酶的时空动态。

IF 7.4 1区生物学

Journal of Cell Biology Pub Date : 2025-02-03 Epub Date: 2024-11-18 DOI: 10.1083/jcb.202312099

Christopher G Sorensen Turpin, Dillon Sloan, Marian LaForest, Lindsey Klebanow, Diana Mitchell, Aaron F Severson, Joshua N Bembenek

{"title":"Securin regulates the spatiotemporal dynamics of separase.","authors":"Christopher G Sorensen Turpin, Dillon Sloan, Marian LaForest, Lindsey Klebanow, Diana Mitchell, Aaron F Severson, Joshua N Bembenek","doi":"10.1083/jcb.202312099","DOIUrl":"10.1083/jcb.202312099","url":null,"abstract":"Separase regulates multiple aspects of the metaphase-to-anaphase transition. Separase cleaves cohesin to allow chromosome segregation and localizes to vesicles to promote exocytosis. The anaphase-promoting complex/cyclosome (APC/C) activates separase by ubiquitinating its inhibitory chaperone, securin, triggering its degradation. How this pathway controls the exocytic function of separase is unknown. During meiosis I, securin is degraded over several minutes, while separase rapidly relocalizes from kinetochore structures at the spindle and cortex to sites of action on chromosomes and vesicles at anaphase onset. The loss of cohesin coincides with the relocalization of separase to the chromosome midbivalent at anaphase onset. APC/C depletion prevents separase relocalization, while securin depletion causes precocious separase relocalization. Expression of non-degradable securin inhibits chromosome segregation, exocytosis, and separase localization to vesicles but not to the anaphase spindle. We conclude that APC/C-mediated securin degradation controls separase localization. This spatiotemporal regulation will impact the effective local concentration of separase for more precise targeting of substrates in anaphase.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 2","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Real-time imaging reveals a role for macrophage protrusive motility in melanoma invasion. 实时成像揭示了巨噬细胞在黑色素瘤侵袭中的突出运动作用。

IF 7.4 1区生物学

Journal of Cell Biology Pub Date : 2025-02-03 Epub Date: 2024-11-21 DOI: 10.1083/jcb.202403096

Gayathri Ramakrishnan, Veronika Miskolci, Miranda Hunter, Morgan A Giese, Daniela Münch, Yiran Hou, Kevin W Eliceiri, Michael R Lasarev, Richard M White, Anna Huttenlocher

引用次数: 0

Activation of lysosomal Ca2+ channels mitigates mitochondrial damage and oxidative stress. 激活溶酶体 Ca2+ 通道可减轻线粒体损伤和氧化应激。

IF 7.4 1区生物学

Journal of Cell Biology Pub Date : 2025-01-06 Epub Date: 2024-11-05 DOI: 10.1083/jcb.202403104

Xinghua Feng, Weijie Cai, Qian Li, Liding Zhao, Yaping Meng, Haoxing Xu

{"title":"Activation of lysosomal Ca2+ channels mitigates mitochondrial damage and oxidative stress.","authors":"Xinghua Feng, Weijie Cai, Qian Li, Liding Zhao, Yaping Meng, Haoxing Xu","doi":"10.1083/jcb.202403104","DOIUrl":"10.1083/jcb.202403104","url":null,"abstract":"Elevated levels of plasma-free fatty acids and oxidative stress have been identified as putative primary pathogenic factors in endothelial dysfunction etiology, though their roles are unclear. In human endothelial cells, we found that saturated fatty acids (SFAs)-including the plasma-predominant palmitic acid (PA)-cause mitochondrial fragmentation and elevation of intracellular reactive oxygen species (ROS) levels. TRPML1 is a lysosomal ROS-sensitive Ca2+ channel that regulates lysosomal trafficking and biogenesis. Small-molecule agonists of TRPML1 prevented PA-induced mitochondrial damage and ROS elevation through activation of transcriptional factor EB (TFEB), which boosts lysosome biogenesis and mitophagy. Whereas genetically silencing TRPML1 abolished the protective effects of TRPML1 agonism, TRPML1 overexpression conferred a full resistance to PA-induced oxidative damage. Pharmacologically activating the TRPML1-TFEB pathway was sufficient to restore mitochondrial and redox homeostasis in SFA-damaged endothelial cells. The present results suggest that lysosome activation represents a viable strategy for alleviating oxidative damage, a common pathogenic mechanism of metabolic and age-related diseases.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

PI(3,5)P2 asymmetry during mitosis is essential for asymmetric vacuolar inheritance. 有丝分裂过程中PI(3,5)P2的不对称性对不对称空泡遗传至关重要。

IF 4.4 1区生物学

Journal of Cell Biology Pub Date : 2025-01-06 Epub Date: 2024-11-08 DOI: 10.1083/jcb.202406170

Mariam Huda, Mukadder Koyuncu, Cansu Dilege, Ayse Koca Caydasi

{"title":"PI(3,5)P2 asymmetry during mitosis is essential for asymmetric vacuolar inheritance.","authors":"Mariam Huda, Mukadder Koyuncu, Cansu Dilege, Ayse Koca Caydasi","doi":"10.1083/jcb.202406170","DOIUrl":"10.1083/jcb.202406170","url":null,"abstract":"Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) is a low-abundance signaling lipid that plays crucial roles in various cellular processes, including endolysosomal system structure/function, stress response, and cell cycle regulation. PI(3,5)P2 synthesis increases in response to environmental stimuli, yet its behavior in cycling cells under basal conditions remains elusive. Here, we analyzed spatiotemporal changes in PI(3,5)P2 levels during the cell cycle of S. cerevisiae. We found that PI(3,5)P2 accumulates on the vacuole in the daughter cell while it disappears from the vacuole in the mother cell during mitosis. Concomitant with the changes in PI(3,5)P2 distribution, the daughter vacuole became more acidic, whereas the acidity of the mother vacuole decreased during mitosis. Our data further showed that both PI(3,5)P2 and the PI(3,5)P2 effector protein Atg18 are determinants of vacuolar-pH asymmetry and acidity. Our work, thus, identifies PI(3,5)P2 as a key factor for the establishment of vacuolar-pH asymmetry, providing insights into how the mother cell ages while the daughter cell is rejuvenated.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Arrayed CRISPRi library to suppress genes required for Schizosaccharomyces pombe viability. 通过 CRISPRi 文库阵列抑制小鼠酵母生存所需的基因。

IF 7.4 1区生物学

Journal of Cell Biology Pub Date : 2025-01-06 Epub Date: 2024-10-08 DOI: 10.1083/jcb.202404085

Ken Ishikawa, Saeko Soejima, Takashi Nishimura, Shigeaki Saitoh

{"title":"Arrayed CRISPRi library to suppress genes required for Schizosaccharomyces pombe viability.","authors":"Ken Ishikawa, Saeko Soejima, Takashi Nishimura, Shigeaki Saitoh","doi":"10.1083/jcb.202404085","DOIUrl":"10.1083/jcb.202404085","url":null,"abstract":"The fission yeast, Schizosaccharomyces pombe, is an excellent eukaryote model organism for studying essential biological processes. Its genome contains ∼1,200 genes essential for cell viability, most of which are evolutionarily conserved. To study these essential genes, resources enabling conditional perturbation of target genes are required. Here, we constructed comprehensive arrayed libraries of plasmids and strains to knock down essential genes in S. pombe using dCas9-mediated CRISPRi. These libraries cover ∼98% of all essential genes in fission yeast. We estimate that in ∼60% of these strains, transcription of a target gene was repressed so efficiently that cell proliferation was significantly inhibited. To demonstrate the usefulness of these libraries, we performed metabolic analyses with knockdown strains and revealed flexible interaction among metabolic pathways. Libraries established in this study enable comprehensive functional analyses of essential genes in S. pombe and will facilitate the understanding of essential biological processes in eukaryotes.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Kinetochores grip microtubules with directionally asymmetric strength. 动芯以方向不对称的力量抓住微管。

IF 7.4 1区生物学

Journal of Cell Biology Pub Date : 2025-01-06 Epub Date: 2024-11-01 DOI: 10.1083/jcb.202405176

Joshua D Larson, Natalie A Heitkamp, Lucas E Murray, Andrew R Popchock, Sue Biggins, Charles L Asbury

{"title":"Kinetochores grip microtubules with directionally asymmetric strength.","authors":"Joshua D Larson, Natalie A Heitkamp, Lucas E Murray, Andrew R Popchock, Sue Biggins, Charles L Asbury","doi":"10.1083/jcb.202405176","DOIUrl":"10.1083/jcb.202405176","url":null,"abstract":"For accurate mitosis, all chromosomes must achieve \"biorientation,\" with replicated sister chromatids coupled via kinetochores to the plus ends of opposing microtubules. However, kinetochores first bind the sides of microtubules and subsequently find plus ends through a trial-and-error process; accurate biorientation depends on the selective release of erroneous attachments. Proposed mechanisms for error-correction have focused mainly on plus-end attachments. Whether erroneous side attachments are distinguished from correct side attachments is unknown. Here, we show that side-attached kinetochores are very sensitive to microtubule polarity, gripping sixfold more strongly when pulled toward plus versus minus ends. This directionally asymmetric grip is conserved in human and yeast subcomplexes, and it correlates with changes in the axial arrangement of subcomplexes within the kinetochore, suggesting that internal architecture dictates attachment strength. We propose that the kinetochore's directional grip promotes accuracy during early mitosis by stabilizing correct attachments even before both sisters have found plus ends.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

ER export via SURF4 uses diverse mechanisms of both client and coat engagement. 通过 SURF4 输出的 ER 采用了客户和外衣参与的多种机制。

IF 7.4 1区生物学

Journal of Cell Biology Pub Date : 2025-01-06 Epub Date: 2024-11-12 DOI: 10.1083/jcb.202406103

Julija Maldutyte, Xiao-Han Li, Natalia Gomez-Navarro, Evan G Robertson, Elizabeth A Miller

引用次数: 0