Molecular Biology of the Cell最新文献

{"title":"Cul3 substrate adaptor SPOP targets Nup153 for degradation.","authors":"Joseph Y Ong, Mai Abdusamad, Ivan Ramirez, Ankur Gholkar, Xiaoxuan Zhang, Thomas V Gimeno, Jorge Z Torres","doi":"10.1091/mbc.E24-04-0198","DOIUrl":"10.1091/mbc.E24-04-0198","url":null,"abstract":"<p><p>SPOP is a Cul3 substrate adaptor responsible for the degradation of many proteins related to cell growth and proliferation. Because mutation or misregulation of SPOP drives cancer progression, understanding the suite of SPOP substrates is important to understanding the regulation of cell proliferation. Here, we identify Nup153, a component of the nuclear basket of the nuclear pore complex, as a novel substrate of SPOP. SPOP and Nup153 bind to each other and colocalize at the nuclear envelope and some nuclear foci in cells. The binding interaction between SPOP and Nup153 is complex and multivalent. Nup153 is ubiquitylated and degraded upon expression of SPOP^WT but not its substrate binding-deficient mutant SPOP^F102C. Depletion of SPOP via RNAi leads to Nup153 stabilization. Upon loss of SPOP activity, the nuclear envelope localization of spindle assembly checkpoint protein Mad1, which is tethered to the nuclear envelope by Nup153, is stronger. Altogether, our results demonstrate that SPOP regulates Nup153 levels and expands our understanding of the role of SPOP in protein and cellular homeostasis.</p>","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar24"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MAL2 and rab17 selectively redistribute invadopodia proteins to laterally-induced protrusions in hepatocellular carcinoma cells.","authors":"Saniya S Davis, Lauren R Bassaro, Pamela L Tuma","doi":"10.1091/mbc.E24-09-0400","DOIUrl":"10.1091/mbc.E24-09-0400","url":null,"abstract":"<p><p>MAL2 (myelin and lymphocyte protein 2) and rab17 have been identified as hepatocellular carcinoma tumor suppressors. However, little is known how their functions in hepatic polarized protein sorting/trafficking translate into how they function in the epithelial-to-mesenchymal transition and/or the mesenchymal-to-epithelial transition in metastases. To investigate this, we expressed MAL2 and rab17 alone or together in hepatoma-derived Clone 9 cells (that lack endogenous MAL2 and rab17). Like MAL2, we found that rab17 expression led to the formation of actin- and cholesterol-dependent protrusions that correlated to its anti-oncogenic properties. MAL2 or rab17 selectively promoted the redistribution of invadopodia proteins to the protrusion tips that correlated with decreased matrix degradation. MAL2-mediated redistribution required a putative EVH1 recognition motif whereas rab17-mediated redistribution was GTP dependent. We also determined that MAL2 and rab17 interaction was GTP dependent, but not dependent on the MAL2 EVH1 recognition motifs, and that protrusions formed by their combined expression shared features of those induced by either alone. Finally, we report that MAL2 or rab17 can redirect trafficking of newly synthesized membrane proteins from the Golgi to the induced protrusions and that the EVH1 recognition motif was required in MAL2 and that rab17-mediated trafficking was GTP dependent.</p>","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar26"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The adoption of the braided river model toward an inclusive STEM workforce for all.","authors":"Aixa Alemán-Díaz, Sakib Hussen, Abdul Siam, Candice M Etson, Robin McC Greenler, Taylor Lightner, Semarhy Quiñones-Soto, Simone B Soso, Verónica A Segarra","doi":"10.1091/mbc.E24-09-0416","DOIUrl":"10.1091/mbc.E24-09-0416","url":null,"abstract":"<p><p>Despite decades of interventions aiming to transform the science, technology, engineering, and mathematics (STEM) workforce to be more inclusive and diverse, little progress has been made in creating long-lasting, sustainable change. For a long period of time, the STEM workforce has been described as a leaky pipeline. While there has been some utility to thinking about the STEM workforce in this way, in this article, we discuss how characterizing the STEM workforce as a leaky pipeline can impede the design of innovative interventions that contribute to sustainable change toward a more inclusive scientific enterprise. As an alternative, we join others in proposing the braided river ecosystem model, related social sciences and career development theories as more inclusive ways to think about the STEM workforce and how a target group or an individual navigates their career choices and development as a scientist. New models and paradigms to understand the STEM workforce and individuals' careers in science may open the door to finding novel strategies to make careers in STEM accessible to all. We present case studies demonstrating the practical applications of these inclusive models.</p>","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":"36 3","pages":"vo1"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA damage causes ATM-dependent heterochromatin loss leading to nuclear softening, blebbing, and rupture.","authors":"Nebiyat Eskndir, Manseeb Hossain, Marilena L Currey, Mai Pho, Yasmin Berrada, Katie Lin, Gianna Manning, Kelsey Prince, Andrew D Stephens","doi":"10.1091/mbc.E24-05-0232","DOIUrl":"10.1091/mbc.E24-05-0232","url":null,"abstract":"<p><p>The nucleus must maintain stiffness to preserve its shape and integrity to ensure proper function. Defects in nuclear stiffness caused from chromatin and lamin perturbations produce abnormal nuclear shapes common in aging, heart disease, and cancer. Loss of nuclear shape via protrusions called blebs lead to nuclear rupture that is well established to cause nuclear dysfunction, including DNA damage. However, it remains unknown how increased DNA damage affects nuclear stiffness, shape, and ruptures, which could create a feedback loop. To determine whether increased DNA damage alters nuclear physical properties, we treated mouse embryonic fibroblast cells with DNA damage drugs cisplatin and bleomycin. DNA damage drugs caused increased nuclear blebbing and rupture in interphase nuclei within a few hours and independent of mitosis. Micromanipulation force measurements reveal that DNA damage decreased chromatin-based nuclear mechanics but did not change lamin-based strain stiffening at long extensions relative to wild type. Immunofluorescence measurements of DNA damage treatments reveal the mechanism is an ATM-dependent decrease in heterochromatin leading to nuclear weaken, blebbing, and rupture which can be rescued upon ATM inhibition treatment. Thus, DNA damage drugs cause ATM-dependent heterochromatin loss resulting in nuclear softening, blebbing, and rupture.</p>","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"br6"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TgGloL is an atypical glyoxalase/VOC domain-containing apicoplast protein that is important for the growth of <i>Toxoplasma</i>.","authors":"Syrian G Sanchez, Esther Pouzet, Loïc Guimbaud, Arnault Graindorge, Laurence Berry, Sébastien Besteiro","doi":"10.1091/mbc.E24-09-0391","DOIUrl":"10.1091/mbc.E24-09-0391","url":null,"abstract":"<p><p>Glycolysis is a conserved metabolic pathway that converts glucose into pyruvate in the cytosol, producing ATP and NADH. In <i>Toxoplasma gondii</i> and several other apicomplexan parasites, some glycolytic enzymes have isoforms located in their plastid (called the apicoplast). In this organelle, glycolytic intermediates like glyceraldehyde 3-phosphate (GAP) and dihydroxyacetone phosphate (DHAP) are imported from the cytosol and further metabolized, providing ATP, reducing power, and precursors for anabolic pathways such as isoprenoid synthesis. However, GAP and DHAP can spontaneously convert into methylglyoxal, a toxic by-product detoxified by the glyoxalase system, typically involving Glyoxalase-1 (Glo-1) and Glyoxalase-2 (Glo-2). In <i>T. gondii</i>, we identified an atypical protein, TgGloL, containing a Glo-1-like motif but with limited homology to typical Glo enzymes. TgGloL localizes to the apicoplast, and its conditional knockdown impairs parasite growth, indicating its importance. While a specific and direct role for TgGloL in methylglyoxal detoxification within the apicoplast remains unclear, it is crucial for maintaining organelle homeostasis and for overall parasite fitness.</p>","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar32"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Close cooperation between Semi1 and Semi2 proteins is essential for pronuclear positioning in <i>Tetrahymena thermophila</i>.","authors":"Takahiko Akematsu, Josef Loidl, Yasuhiro Fukuda, Masaaki Iwamoto","doi":"10.1091/mbc.E24-11-0503","DOIUrl":"10.1091/mbc.E24-11-0503","url":null,"abstract":"<p><p>During sexual reproduction in the ciliate <i>Tetrahymena thermophila</i>, meiosis occurs in the germline micronucleus, resulting in the formation of four haploid micronuclei. Of these, only one is selected to evade autophagy, and subsequently migrates to the membrane junction with the partner cell for reciprocal pronuclear exchange. We previously demonstrated that the transmembrane protein Semi1 is essential for this nuclear migration. Semi1 is specifically expressed in mating cells and localizes to the periphery of the selected nucleus. Loss of Semi1 disrupts nuclear attachment to the junction, leading to infertility. However, the mechanism by which Semi1 positions the nucleus at the junction remains unclear. Here, we report that the Semi1-interacting protein, Semi2, is also necessary for proper nuclear positioning. Deletion of Semi2 results in the same nuclear mislocalization phenotype and infertility observed in Semi1 mutant cells. Semi2 colocalizes with Semi1, but in the absence of Semi1, Semi2 fails to exhibit perinuclear localization. The selected nucleus anchors to microtubules prior to migration, a process dependent on both Semi1 and Semi2. We propose a model in which Semi1 recruits Semi2 to the selected nucleus, facilitating the interaction between the nucleus and microtubules required for proper nuclear positioning at the membrane junction.</p>","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar23"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fission yeast GPI inositol deacylase Bst1 regulates ER-Golgi transport and functions in late stages of cytokinesis.","authors":"Yanfang Ye, Aysha H Osmani, Zhen-Ru Liu, Addie Kern, Jian-Qiu Wu","doi":"10.1091/mbc.E24-08-0375","DOIUrl":"10.1091/mbc.E24-08-0375","url":null,"abstract":"<p><p>The Munc13/UNC-13 family protein Ync13 is essential for septum integrity and cytokinesis in fission yeast. To further explore the mechanism of Ync13 functions, spontaneous suppressors of <i>ync13</i> mutants, which can suppress the colony-formation defects and lysis phenotype of <i>ync13</i> mutant cells, are isolated and characterized. One of the suppressor mutants, <i>bst1</i>-<i>s27</i>, shows defects in the cytokinetic contractile ring constriction, septation, and daughter cell separation, similar to <i>bst1Δ</i> mutant. Bst1, a predicted GPI inositol deacylase, was an uncharacterized protein in fission yeast. It localizes to ER and puncta structures in the cytoplasm. The Bst1 puncta overlaps frequently with Anp1, which is a marker of endoplasmic reticulum (ER)-Golgi transport, but rarely with trans-Golgi marker Sec72. The nuclear ER signal of Anp1 increases in <i>bst1Δ</i> mutant, whereas Sec72 localization shows no obvious changes. In addition, more cytoplasmic puncta structures of COPII subunits, Sec13 and Sec24, are observed in <i>bst1Δ</i> mutant, and acid phosphatase secretion is compromised without Bst1. Consistently, the division site targeting of the β-glucanase Eng1 and α-glucanase Agn1 is reduced in <i>bst1Δ</i> and <i>bst1Δ ync13Δ</i> mutant. Taken together, our results suggest that Bst1 regulates ER-Golgi transport and is involved in cytokinesis through regulating the secretion of glucanases.</p>","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar27"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SYS-1/beta-catenin inheritance and regulation by Wnt signaling during asymmetric cell division.","authors":"Maria F Valdes Michel, Bryan T Phillips","doi":"10.1091/mbc.E24-10-0441","DOIUrl":"10.1091/mbc.E24-10-0441","url":null,"abstract":"<p><p>Asymmetric cell division (ACD) allows daughter cells of a polarized mother to acquire different developmental fates. In <i>Caenorhabditis elegans</i>, the Wnt/β-catenin Asymmetry (WβA) pathway regulates many embryonic and larval ACDs; here, a Wnt gradient induces an asymmetric distribution of Wnt signaling components within the dividing mother cell. One terminal nuclear effector of the WβA pathway is the transcriptional activator SYS-1/β-catenin. SYS-1 is sequentially negatively regulated during ACD; first by centrosomal regulation and subsequent proteasomal degradation and second by asymmetric activity of the β-catenin \"destruction complex\" in one of the two daughter cells, which decreases SYS-1 levels in the absence of WβA signaling. However, the extent to which mother cell SYS-1 influences cell fate decisions of the daughters is unknown. Here, we quantify inherited SYS-1 in the differentiating daughter cells and the role of SYS-1 inheritance in Wnt-directed ACD. Photobleaching experiments demonstrate the GFP::SYS-1 present in daughter cell nuclei is comprised of inherited and <i>de novo</i> translated SYS-1 pools. We used a photoconvertible DENDRA2::SYS-1, to directly observe the dynamics of inherited SYS-1. Photoconversion during mitosis reveals that SYS-1 clearance at the centrosome preferentially degrades older SYS-1 and that newly localized centrosomal SYS-1 depends on dynein trafficking. Photoconversion of DENDRA2::SYS-1 in the EMS cell during Wnt-driven ACD shows daughter cell inheritance of mother cell SYS-1. Additionally, disrupting centrosomal SYS-1 localization in mother cells increased inherited SYS-1 and, surprisingly, loss of centrosomal SYS-1 also resulted in increased levels of <i>de novo</i> SYS-1 in both EMS daughter cells. Last, we show that negative regulation of SYS-1 in daughter cells via the destruction complex member APR-1/APC is key to limit both the <i>de novo</i> and the inherited SYS-1 pools in both the E and the MS cells. We conclude that regulation of both inherited and newly translated SYS-1 via centrosomal processing in the mother cell and daughter cell regulation via Wnt signaling are critical to maintain sister SYS-1 asymmetry during ACD.</p>","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar25"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Valosin-containing protein p97 extracts capping protein CP110 from the mother centriole to promote ciliogenesis.","authors":"Rahit Dewanji, Naava Naslavsky, Steve Caplan","doi":"10.1091/mbc.E24-10-0455","DOIUrl":"10.1091/mbc.E24-10-0455","url":null,"abstract":"<p><p>The primary cilium is a crucial signaling organelle that can be generated by most human cells, and impediments to primary ciliogenesis lead to a variety of developmental disorders known as ciliopathies. The removal of the capping protein, CP110, from the mother centriole is a key early step that promotes generation of the ciliary vesicle and ciliogenesis. Recent studies have demonstrated that CP110 undergoes polyubiquitination and degradation in the proteosome, but the mechanisms of unfolding and removal from the mother centriole remain unknown. Herein we demonstrate that p97/Valosin-containing protein (VCP or Cdc48), a member of the ATPase Associated with diverse Activities (AAA) protein family, is responsible for removal of CP110 from the mother centriole. We show that use of p97 knockdown or inhibition impairs ciliogenesis, in a mechanism dependent on CP110. Our findings demonstrate a novel role for p97 in the process of primary ciliogenesis, and support a mechanism by which ubiquitinated CP110 is degraded in a process that requires p97-mediated unfolding and removal from the mother centriole.</p>","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"br7"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anillin tunes contractility and regulates barrier function during Rho flare-mediated tight junction remodeling.","authors":"Zie Craig, Torey R Arnold, Kelsey Walworth, Alexander Walkon, Ann L Miller","doi":"10.1091/mbc.E24-11-0513","DOIUrl":"10.1091/mbc.E24-11-0513","url":null,"abstract":"<p><p>To preserve barrier function, cell-cell junctions must dynamically remodel during cell shape changes. We have previously described a rapid tight junction repair pathway characterized by local, transient activations of RhoA, termed \"Rho flares,\" which repair leaks in tight junctions via promoting local actomyosin-mediated junction remodeling. In this pathway, junction elongation is a mechanical trigger that initiates RhoA activation through an influx of intracellular calcium and recruitment of p115RhoGEF. However, mechanisms that tune the level of RhoA activation and Myosin II contractility during the process remain uncharacterized. Here, we show that the scaffolding protein Anillin localizes to Rho flares and regulates RhoA activity and actomyosin contraction at flares. Knocking down Anillin results in Rho flares with increased intensity but shorter duration. These changes in active RhoA dynamics weaken downstream F-actin and Myosin II accumulation at the site of Rho flares, resulting in decreased junction contraction. Consequently, tight junction breaks are not reinforced following Rho flares. We show that Anillin-driven RhoA regulation is necessary for successfully repairing tight junction leaks and protecting junctions from repeated barrier damage. Together, these results uncover a novel regulatory role for Anillin during tight junction repair and barrier function maintenance.</p>","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar31"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}