Alexandru Nita,Sara P Abraham,Eman R Elrefaay,Bohumil Fafilek,Eliska Cizkova,Vlad Constantin Ursachi,Iva Gudernova,Adolf Koudelka,Pooja Dudeja,Tomas Gregor,Zuzana Feketova,Gustavo Rico,Katerina Svozilova,Canan Celiker,Aleksandra A Czyrek,Tomas Barta,Lukas Trantirek,Antoni Wiedlocha,Pavel Krejci,Michaela Bosakova
{"title":"FGFR2 residence in primary cilia is necessary for epithelial cell signaling.","authors":"Alexandru Nita,Sara P Abraham,Eman R Elrefaay,Bohumil Fafilek,Eliska Cizkova,Vlad Constantin Ursachi,Iva Gudernova,Adolf Koudelka,Pooja Dudeja,Tomas Gregor,Zuzana Feketova,Gustavo Rico,Katerina Svozilova,Canan Celiker,Aleksandra A Czyrek,Tomas Barta,Lukas Trantirek,Antoni Wiedlocha,Pavel Krejci,Michaela Bosakova","doi":"10.1083/jcb.202311030","DOIUrl":"https://doi.org/10.1083/jcb.202311030","url":null,"abstract":"Primary cilium projects from cells to provide a communication platform with neighboring cells and the surrounding environment. This is ensured by the selective entry of membrane receptors and signaling molecules, producing fine-tuned and effective responses to the extracellular cues. In this study, we focused on one family of signaling molecules, the fibroblast growth factor receptors (FGFRs), their residence within cilia, and its role in FGFR signaling. We show that FGFR1 and FGFR2, but not FGFR3 and FGFR4, localize to primary cilia of the developing mouse tissues and in vitro cells. For FGFR2, we demonstrate that the ciliary residence is necessary for its signaling and expression of target morphogenic genes. We also show that the pathogenic FGFR2 variants have minimal cilium presence, which can be rescued for the p.P253R variant associated with the Apert syndrome by using the RLY-4008 kinase inhibitor. Finally, we determine the molecular regulators of FGFR2 trafficking to cilia, including IFT144, BBS1, and the conserved T429V430 motif within FGFR2.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"43 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857292","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}
Alexandre Schaeffer,Simona Buracco,Morgan Gazzola,Matthieu Gelin,Benoit Vianay,Chiara de Pascalis,Laurent Blanchoin,Manuel Théry
{"title":"Microtubule-driven cell shape changes and actomyosin flow synergize to position the centrosome.","authors":"Alexandre Schaeffer,Simona Buracco,Morgan Gazzola,Matthieu Gelin,Benoit Vianay,Chiara de Pascalis,Laurent Blanchoin,Manuel Théry","doi":"10.1083/jcb.202405126","DOIUrl":"https://doi.org/10.1083/jcb.202405126","url":null,"abstract":"The regulation of centrosome position is critical to the alignment of intracellular structures with extracellular cues. The exact nature and spatial distribution of the mechanical forces that balance at the centrosome are unknown. Here, we used laser-based nanoablations in adherent cells and found that forces along microtubules were damped by their anchoring to the actin network, rendering them ineffective in moving the microtubule aster. In contrast, the actomyosin contractile network was responsible for the generation of a centripetal flow that robustly drives the centrosome toward the geometrical center of the cell, even in the absence of microtubules. Unexpectedly, we discovered that the remodeling of cell shape around the centrosome was instrumental in aster centering. The radial array of microtubules and cytoplasmic dyneins appeared to direct this reorganization. This revised view of the respective roles of actin and microtubules in centrosome positioning offers a new perspective for understanding the establishment of cell polarity.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"90 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846435","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":"ZBTB17/MIZ1 promotes peroxisome biogenesis by transcriptional regulation of PEX13.","authors":"Hongqin Liu,Xi Chen,Hanlin Wang,Guanglei Zhuang,Zheng-Jiang Zhu,Min Zhuang","doi":"10.1083/jcb.202407198","DOIUrl":"https://doi.org/10.1083/jcb.202407198","url":null,"abstract":"Peroxisomes are integral metabolic organelles involved in both catabolic and anabolic processes in humans, with defects linked to diseases. The functions of peroxisomes are regulated at transcriptional, translational, and posttranslational levels. In this study, we employed the CRISPR/Cas9-based screening of a ubiquitin ligase library to identify regulators of human peroxisomes. We discovered that ZBTB17 (MIZ1) plays a role in regulating the import of proteins into peroxisomes. Independent of its ubiquitin ligase activity, ZBTB17/MIZ1 operates as a transcription factor to modulate the expression of key importer PEX13, influencing the localization of peroxisomal enzymes. Furthermore, metabolomic profiling reveals that knockdown of ZBTB17 or PEX13 results in similar metabolic alterations, with downregulated purine synthesis. Collectively, we identify ZBTB17 as a key regulator of peroxisomal protein import, thereby affecting peroxisomal function and nucleotide metabolism. Our findings provide insights into the multifaceted regulation of peroxisomes in complex human cells and shed light on the molecular mechanisms underlying ZBTB17's role as a transcriptional regulator.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"3 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846283","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}
Ellis G Jaffray,Michael H Tatham,Barbara Mojsa,Anna Plechanovová,Alejandro Rojas-Fernandez,Julio C Y Liu,Niels Mailand,Adel F M Ibrahim,Graeme Ball,Iain M Porter,Ronald T Hay
{"title":"PML mutants from arsenic-resistant patients reveal SUMO1-TOPORS and SUMO2/3-RNF4 degradation pathways.","authors":"Ellis G Jaffray,Michael H Tatham,Barbara Mojsa,Anna Plechanovová,Alejandro Rojas-Fernandez,Julio C Y Liu,Niels Mailand,Adel F M Ibrahim,Graeme Ball,Iain M Porter,Ronald T Hay","doi":"10.1083/jcb.202407133","DOIUrl":"https://doi.org/10.1083/jcb.202407133","url":null,"abstract":"Arsenic effectively treats acute promyelocytic leukemia by inducing SUMO and ubiquitin-dependent degradation of the promyelocytic leukemia (PML)-retinoic acid receptor alpha oncogenic fusion protein. However, some patients relapse with arsenic-resistant disease because of missense mutations in PML. To determine the mechanistic basis for arsenic resistance, PML-/- cells were reconstituted with YFP fusions of wild-type PML-V and two common patient mutants: A216T and L217F. Both mutants were resistant to degradation by arsenic but for different biochemical reasons. Arsenic did not trigger SUMOylation of A216T PML, which failed to recruit the SUMO-targeting ubiquitin ligases RNF4 and TOPORS. L217F PML did respond with increased SUMO2/3 conjugation that facilitated RNF4 engagement but failed to reach the threshold of SUMO1 conjugation required to recruit TOPORS. Thus, neither mutant accumulated the appropriate polyubiquitin signal required for p97 binding. These PML mutants have revealed a convergence of SUMO1, SUMO2/3, TOPORS, and RNF4 that facilitates the arsenic-induced degradation of PML.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"65 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846433","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":"Mitochondrial mayhem: Disrupting conserved N-terminal motifs in TANGO2 impacts its localization and function.","authors":"Sarah E Sandkuhler,Samuel J Mackenzie","doi":"10.1083/jcb.202503010","DOIUrl":"https://doi.org/10.1083/jcb.202503010","url":null,"abstract":"TANGO2 deficiency in humans leads to progressive neurological impairment, punctuated by life-threatening metabolic crises. In this issue, Lujan and colleagues demonstrate that TANGO2 localizes within the mitochondrial lumen and binds acyl-CoA species, potentially implicating it as a lipid trafficking protein.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"27 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836604","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":"Rab GTPases as \"eat me\" signals for selective autophagy.","authors":"Yan G Zhao","doi":"10.1083/jcb.202502030","DOIUrl":"https://doi.org/10.1083/jcb.202502030","url":null,"abstract":"Selective autophagy targets specific cellular cargo for degradation. In this issue, Zhao et al. (https://doi.org/10.1083/jcb.202410150) uncovered that Rab GTPases serve as pivotal \"autophagy cues\" for recruitment of cargo receptors to facilitate mitophagy, lipophagy, and xenophagy, contributing to the precise spatiotemporal regulation of selective autophagy.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"106 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819160","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":"Subversion of the host endocytic pathway by Legionella pneumophila-mediated ubiquitination of Rab5.","authors":"Shino Tanaka, Hiromu Oide, Shumma Ikeda, Mitsuo Tagaya, Hiroki Nagai, Tomoko Kubori, Kohei Arasaki","doi":"10.1083/jcb.202406159","DOIUrl":"10.1083/jcb.202406159","url":null,"abstract":"<p><p>Legionella pneumophila is an intracellular bacterial pathogen that modulates membrane trafficking to survive and proliferate within host cells. After phagocytosis, the L. pneumophila-containing vacuole evades the endocytic pathway by excluding the host GTPase Rab5, a crucial regulator of phagosomal maturation. In this study, we show that the evolutionarily conserved lysine residue K134 of Rab5 undergoes ubiquitination during infection. This modification depends on Lpg2525, an F-box protein from L. pneumophila that acts as a component of the SKP-Cullin-F-box complex. We further demonstrate that Rab5 ubiquitination facilitates the recruitment of RabGAP-5, a Rab5-specific GAP, leading to Rab5 inactivation and subsequent release from the bacterial vacuole. Importantly, the K134 Rab5 mutant limits L. pneumophila replication within host cells. These findings reveal that Lpg2525-mediated Rab5 ubiquitination is a key survival strategy employed by L. pneumophila in infected host cells.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 4","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541835","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}
Felipe Leon-Diaz, Célia Chamontin, Sébastien Lainé, Marius Socol, Edouard Bertrand, Marylène Mougel
{"title":"Translation of unspliced retroviral genomic RNA in the host cell is regulated in both space and time.","authors":"Felipe Leon-Diaz, Célia Chamontin, Sébastien Lainé, Marius Socol, Edouard Bertrand, Marylène Mougel","doi":"10.1083/jcb.202405075","DOIUrl":"10.1083/jcb.202405075","url":null,"abstract":"<p><p>Retroviruses carry a genomic intron-containing RNA with a long structured 5'-untranslated region, which acts either as a genome encapsidated in the viral progeny or as an mRNA encoding the key structural protein, Gag. We developed a single-molecule microscopy approach to simultaneously visualize the viral mRNA and the nascent Gag protein during translation directly in the cell. We found that a minority of the RNA molecules serve as mRNA and that they are translated in a fast and efficient process. Surprisingly, viral polysomes were also observed at the cell periphery, indicating that translation is regulated in both space and time. Virus translation near the plasma membrane may benefit from reduced competition for ribosomes with most cellular cytoplasmic mRNAs. In addition, local and efficient translation must spare energy to produce Gag proteins, where they accumulate to assemble new viral particles, potentially allowing the virus to evade the host's antiviral defenses.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 4","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046922","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}
Jieqiong Gao, Rico Franzkoch, Cristian Rocha-Roa, Olympia Ekaterini Psathaki, Michael Hensel, Stefano Vanni, Christian Ungermann
{"title":"Any1 is a phospholipid scramblase involved in endosome biogenesis.","authors":"Jieqiong Gao, Rico Franzkoch, Cristian Rocha-Roa, Olympia Ekaterini Psathaki, Michael Hensel, Stefano Vanni, Christian Ungermann","doi":"10.1083/jcb.202410013","DOIUrl":"10.1083/jcb.202410013","url":null,"abstract":"<p><p>Endosomes are central organelles in the recycling and degradation of receptors and membrane proteins. Once endocytosed, such proteins are sorted at endosomes into intraluminal vesicles (ILVs). The resulting multivesicular bodies (MVBs) then fuse with the lysosomes, leading to the degradation of ILVs and recycling of the resulting monomers. However, the biogenesis of MVBs requires a constant lipid supply for efficient ILV formation. An ER-endosome membrane contact site has been suggested to play a critical role in MVB biogenesis. Here, we identify Any1 as a novel phospholipid scramblase, which functions with the lipid transfer protein Vps13 in MVB biogenesis. We uncover that Any1 cycles between the early endosomes and the Golgi and colocalizes with Vps13, possibly at a here-discovered potential contact site between lipid droplets (LDs) and endosomes. Strikingly, both Any1 and Vps13 are required for MVB formation, presumably to couple lipid flux with membrane homeostasis during ILV formation and endosome maturation.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 4","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567218","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}
Ya-Ting Chang, Benjamin A Barad, Juliette Hamid, Hamidreza Rahmani, Brian M Zid, Danielle A Grotjahn
{"title":"Cytoplasmic ribosomes on mitochondria alter the local membrane environment for protein import.","authors":"Ya-Ting Chang, Benjamin A Barad, Juliette Hamid, Hamidreza Rahmani, Brian M Zid, Danielle A Grotjahn","doi":"10.1083/jcb.202407110","DOIUrl":"10.1083/jcb.202407110","url":null,"abstract":"<p><p>Most of the mitochondria proteome is nuclear-encoded, synthesized by cytoplasmic ribosomes, and targeted to the mitochondria posttranslationally. However, a subset of mitochondrial-targeted proteins is imported co-translationally, although the molecular mechanisms governing this process remain unclear. We employ cellular cryo-electron tomography to visualize interactions between cytoplasmic ribosomes and mitochondria in Saccharomyces cerevisiae. We use surface morphometrics tools to identify a subset of ribosomes optimally oriented on mitochondrial membranes for protein import. This allows us to establish the first subtomogram average structure of a cytoplasmic ribosome at the mitochondrial surface in the native cellular context, which showed three distinct connections with the outer mitochondrial membrane surrounding the peptide exit tunnel. Further, this analysis demonstrated that cytoplasmic ribosomes primed for mitochondrial protein import cluster on the outer mitochondrial membrane at sites of local constrictions of the outer and inner mitochondrial membranes. Overall, our study reveals the architecture and the spatial organization of cytoplasmic ribosomes at the mitochondrial surface, providing a native cellular context to define the mechanisms that mediate efficient mitochondrial co-translational protein import.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 4","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567220","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}