{"title":"The PAX3-FOXO1 fusion gene reduces cell-ECM interactions and TGFβ signaling in rhabdomyosarcoma.","authors":"Antonios Chronopoulos,Ivan Chavez,Chandra Kaladhar Vemula,Nikhil Mittal,Vic Zamloot,Yuanzhong Pan,Sangyoon J Han,JinSeok Park","doi":"10.1083/jcb.202408155","DOIUrl":"https://doi.org/10.1083/jcb.202408155","url":null,"abstract":"We identify downregulation of genes related to cell-ECM interactions and TGFβ signaling in FPRMS. We confirm that TGFβ signaling enhances cell-ECM interactions in FNRMS, utilizing confocal reflection microscopy to assess ECM remodeling, and a live-cell sensor to quantitatively assess TGFβ signaling. We also show that PAX3-FOXO1 increases NOS1 expression, stimulating nitric oxide synthesis, which inhibits TGFβ signaling and reduces cell-ECM interactions. We suggest that PAX3-FOXO1 reprograms ECM anchorage dependence by suppressing cell-ECM interactions. The fusion gene can determine sensitivity to growth inhibition via targeted disruption of cell-ECM interactions or TGFβ signaling. Reduced anchorage reliance by the gene may allow cells to survive in circulation and enhance FPRMS metastatic potential.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"27 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521501","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}
{"title":"PLK-1 suppresses centrosome maturation and microtubule polymerization to ensure faithful oocyte meiosis.","authors":"Juhi G Narula,Sarah M Wignall","doi":"10.1083/jcb.202503080","DOIUrl":"https://doi.org/10.1083/jcb.202503080","url":null,"abstract":"Sexual reproduction relies on meiosis, a specialized cell division program that produces haploid gametes. Oocytes of most organisms lack centrosomes, and therefore chromosome segregation is mediated by acentrosomal spindles. Here, we explore the role of Polo-like kinase 1 (PLK-1) in Caenorhabditiselegans oocytes, revealing mechanisms that ensure the fidelity of this unique form of cell division. Previously, PLK-1 was shown to be required for nuclear envelope breakdown and chromosome segregation in oocytes. We now find that PLK-1 is also required for establishing and maintaining acentrosomal spindle organization and for preventing excess microtubule polymerization in these cells. Additionally, our studies revealed an unexpected new role for this essential kinase. While PLK-1 is known to be required for centrosome maturation during mitosis, we found that either removal of PLK-1 from oocytes or inhibition of its kinase activity caused premature recruitment of pericentriolar material to the sperm-provided centrioles following fertilization. Thus, PLK-1 suppresses centrosome maturation during oocyte meiosis, which is opposite to its role in mitosis. Taken together, our work identifies PLK-1 as a key player that promotes faithful acentrosomal meiosis in oocytes and demonstrates that its catalytic activity is required for carrying out these important roles.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"18 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504631","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}
Davide A Basello,Michaela Blažíková,Adriana Roithová,Martina Hálová,Nenad Radivojević,Karla M Neugebauer,David Staněk
{"title":"Dynamic interaction of spliceosomal snRNPs with coilin explains Cajal body characteristics.","authors":"Davide A Basello,Michaela Blažíková,Adriana Roithová,Martina Hálová,Nenad Radivojević,Karla M Neugebauer,David Staněk","doi":"10.1083/jcb.202309128","DOIUrl":"https://doi.org/10.1083/jcb.202309128","url":null,"abstract":"The Cajal body (CB) is a conserved non-membrane nuclear structure where several steps of small nuclear RNP particle (snRNP) biogenesis take place. It has been proposed that CB formation follows a liquid-liquid phase separation model, but this hypothesis has never been rigorously tested. Here, we applied live-cell imaging to show that the key CB assembly factor coilin is mobile within the CB, and we revealed a diffusion barrier that limits the coilin exchange between CBs and the nucleoplasm. We generated single aa mutations and demonstrated that RNA-dependent coilin oligomerization and coilin interaction with snRNP are essential for CB formation and maintenance. We applied these data to formulate a mathematical model that links the movement of coilin within the nucleoplasm, CB, and across the boundary with its oligomerization and snRNP binding. Our results illustrate CB as a structure dynamically responding to snRNP assembly and recycling.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"13 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478643","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}
{"title":"Acidosis attenuates the hypoxic stabilization of HIF-1α by activating lysosomal degradation.","authors":"Bobby White,Zhenyi Wang,Matthew Dean,Johanna Michl,Natalia Nieora,Sarah Flannery,Iolanda Vendrell,Roman Fischer,Alzbeta Hulikova,Pawel Swietach","doi":"10.1083/jcb.202409103","DOIUrl":"https://doi.org/10.1083/jcb.202409103","url":null,"abstract":"Hypoxia-inducible factors (HIFs) mediate cellular responses to low oxygen, notably enhanced fermentation that acidifies poorly perfused tissues and may eventually become more damaging than adaptive. How pH feeds back on hypoxic signaling is unclear but critical to investigate because acidosis and hypoxia are mechanistically coupled in diffusion-limited settings, such as tumors. Here, we examined the pH sensitivity of hypoxic signaling in colorectal cancer cells that can survive acidosis. HIF-1α stabilization under acidotic hypoxia was transient, declining over 48 h. Proteomic analyses identified responses that followed HIF-1α, including canonical HIF targets (e.g., CA9, PDK1), but these did not reflect a proteome-wide downregulation. Enrichment analyses suggested a role for lysosomal degradation. Indeed, HIF-1α destabilization was blocked by inactivating lysosomes, but not proteasome inhibitors. Acidotic hypoxia stimulated lysosomal activity and autophagy via mammalian target of rapamycin complex I (mTORC1), resulting in HIF-1α degradation. This response protects cells from excessive acidification by unchecked fermentation. Thus, alkaline conditions are permissive for at least some aspects of HIF-1α signaling.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"19 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370325","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}
{"title":"Cellular wound healing: A two-step mechanism of plasma membrane repair by annexins and calpains.","authors":"Sabina Elmi,Jesper Nylandsted","doi":"10.1083/jcb.202505027","DOIUrl":"https://doi.org/10.1083/jcb.202505027","url":null,"abstract":"In this issue, Williams et al. (https://doi.org/10.1083/jcb.202408159) reveal a two-step plasma membrane repair process upon injury: annexins first stabilize damage sites, then calcium-activated calpains cleave these patches, triggering microvesicle shedding-mirroring the clot-and-scab resolution seen in tissue-level wound healing.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"600 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320099","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}
{"title":"The primary cilium as a gatekeeper of FGFR2 function.","authors":"Raman Kaushik,Raj K Ladher","doi":"10.1083/jcb.202505022","DOIUrl":"https://doi.org/10.1083/jcb.202505022","url":null,"abstract":"In this issue, Nita et al. (https://doi.org/10.1083/jcb.202311030) show that the primary cilium regulates FGFR2 signalling through spatial compartmentalization, enabling selective downstream activation. Disruption of ciliary localization in disease-linked FGFR2 variants highlights the role of the cilium as a signalling gatekeeper in development and disease.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"44 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320100","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}
Kangfu Peng, Guoxiu Zhao, Hongyu Zhao, Nobuo N Noda, Hong Zhang
{"title":"The autophagy protein ATG-9 regulates lysosome function and integrity.","authors":"Kangfu Peng, Guoxiu Zhao, Hongyu Zhao, Nobuo N Noda, Hong Zhang","doi":"10.1083/jcb.202411092","DOIUrl":"10.1083/jcb.202411092","url":null,"abstract":"<p><p>The transmembrane autophagy protein ATG9 has multiple functions essential for autophagosome formation. Here, we uncovered a novel function of ATG-9 in regulating lysosome biogenesis and integrity in Caenorhabditis elegans. Through a genetic screen, we identified that mutations attenuating the lipid scrambling activity of ATG-9 suppress the autophagy defect in epg-5 mutants, in which non-degradative autolysosomes accumulate. The scramblase-attenuated ATG-9 mutants promote lysosome biogenesis and delivery of lysosome-localized hydrolases and also facilitate the maintenance of lysosome integrity. Through manipulation of phospholipid levels, we found that a reduction in phosphatidylethanolamine (PE) also suppresses the autophagy defects and lysosome damage associated with impaired lysosomal degradation. Our results reveal that modulation of phospholipid composition and distribution, e.g., by attenuating the scramblase activity of ATG-9 or reducing the PE level, regulates lysosome function and integrity.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 6","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11980680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811521","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}
Sandhya Srinivasan, William Ramos-Lewis, Mychel R P T Morais, Qiuyi Chi, Adam W J Soh, Emily Williams, Rachel Lennon, David R Sherwood
{"title":"A collagen IV fluorophore knock-in toolkit reveals trimer diversity in C. elegans basement membranes.","authors":"Sandhya Srinivasan, William Ramos-Lewis, Mychel R P T Morais, Qiuyi Chi, Adam W J Soh, Emily Williams, Rachel Lennon, David R Sherwood","doi":"10.1083/jcb.202412118","DOIUrl":"10.1083/jcb.202412118","url":null,"abstract":"<p><p>The type IV collagen triple helix, composed of three ⍺-chains, is a core basement membrane (BM) component that assembles into a network within BMs. Endogenous tagging of all ⍺-chains with genetically encoded fluorophores has remained elusive, limiting our understanding of this crucial BM component. Through genome editing, we show that the C termini of the C. elegans type IV collagen ⍺-chains EMB-9 and LET-2 can be fused to a variety of fluorophores to create a strain toolkit with wild-type health. Using quantitative imaging, our results suggest a preference for LET-2-LET-2-EMB-9 trimer construction, but also tissue-specific flexibility in trimers assembled driven by differences in ⍺-chain expression levels. By tagging emb-9 and let-2 mutants that model human Gould syndrome, a complex multitissue disorder, we further discover defects in extracellular accumulation and turnover that might help explain disease pathology. Together, our findings identify a permissive tagging site in C. elegans that will allow diverse studies on type IV collagen regulation and function in animals.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 6","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11917169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656812","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}
Rong Sun, James P Allen, Zhuqing Mao, Liana Wilson, Mariam Haider, Baris Alten, Zimeng Zhou, Xinyi Wang, Qiangjun Zhou
{"title":"The postsynaptic density in excitatory synapses is composed of clustered, heterogeneous nanoblocks.","authors":"Rong Sun, James P Allen, Zhuqing Mao, Liana Wilson, Mariam Haider, Baris Alten, Zimeng Zhou, Xinyi Wang, Qiangjun Zhou","doi":"10.1083/jcb.202406133","DOIUrl":"10.1083/jcb.202406133","url":null,"abstract":"<p><p>The nanoscale organization of proteins within synapses is critical for maintaining and regulating synaptic transmission and plasticity. Here, we used cryo-electron tomography (cryo-ET) to directly visualize the three-dimensional architecture and supramolecular organization of postsynaptic components in both synaptosomes and synapses from cultured neurons. Cryo-ET revealed that postsynaptic density (PSD) is composed of membrane-associated nanoblocks of various sizes. Subtomogram averaging from synaptosomes showed two types (type A and B) of postsynaptic receptor-like particles at resolutions of 24 and 26 Å, respectively. Furthermore, our analysis suggested that potential presynaptic release sites are closer to nanoblocks with type A/B receptor-like particles than to nanoblocks without type A/B receptor-like particles. The results of this study provide a more comprehensive understanding of synaptic ultrastructure and suggest that PSD is composed of clustering of various nanoblocks. These nanoblocks are heterogeneous in size, assembly, and distribution, which likely contribute to the dynamic nature of PSD in modulating synaptic strength.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 6","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719375","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}
Julio Miranda-Alban, Nicelio Sanchez-Luege, Fernando M Valbuena, Chyan Rangel, Ilaria Rebay
{"title":"The Abelson kinase and the Nedd4 family E3 ligases co-regulate Notch trafficking to limit signaling.","authors":"Julio Miranda-Alban, Nicelio Sanchez-Luege, Fernando M Valbuena, Chyan Rangel, Ilaria Rebay","doi":"10.1083/jcb.202407066","DOIUrl":"10.1083/jcb.202407066","url":null,"abstract":"<p><p>Precise output from the conserved Notch signaling pathway governs a plethora of cellular processes and developmental transitions. Unlike other pathways that use a cytoplasmic relay, the Notch cell surface receptor transduces signaling directly to the nucleus, with endocytic trafficking providing critical regulatory nodes. Here we report that the cytoplasmic tyrosine kinase Abelson (Abl) facilitates Notch internalization into late endosomes/multivesicular bodies (LEs), thereby limiting signaling output in both ligand-dependent and -independent contexts. Abl phosphorylates the PPxY motif within Notch, a molecular target for its degradation via Nedd4 family ubiquitin ligases. We show that Su(dx), a family member, mediates the Abl-directed LE regulation of Notch via the PPxY, while another family member, Nedd4Lo, contributes to Notch internalization into LEs through both PPxY-dependent and -independent mechanisms. Our findings demonstrate how a network of posttranslational modifiers converging at LEs cooperatively modulates Notch signaling to ensure the precision and robustness of its cellular and developmental functions.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 6","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780020","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}