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{"title":"Adhesion integrity activates mechanosensitive proliferative signaling.","authors":"Lídia Faria, Carine M Gonçalves, Inês Fidalgo, Carlotta Mix, Maria M Azevedo, Carla S Lopes, Olena Kostylenko, Vanessa Rodrigues, Ricardo Braguês, Paula Sampaio, Sandra Tavares, Vaibhav Mahajan, Anna V Taubenberger, Florence Janody","doi":"10.1083/jcb.202511205","DOIUrl":"https://doi.org/10.1083/jcb.202511205","url":null,"abstract":"<p><p>Weakening of adherens junctions (AJs) and focal adhesions (FAs) adhesiveness has been proposed to enable cancer initiation and progression. Here we report that E-cadherin at cell-cell contacts and vinculin at FAs are transiently under higher tension in MCF10A cells overactivating the Src proto-oncogene. Knockdown of paxillin or P-cadherin, or inhibition of focal adhesion kinase (FAK) or AJ assembly with EGTA, suppresses this force increase across both E-cadherin and vinculin. FAK and P-cadherin trans-homophilic interactions further enhance Src-dependent myosin II and extracellular signal-regulated kinase (ERK) activation. In addition, FAK and P-cadherin potentiate ERK and serum response factor (SRF) signaling, thereby supporting cell proliferation. Furthermore, knockdown of Drosophila cadherin or alpha integrin suppresses Src-induced tissue overgrowth, reinforcing the role of adhesion integrity in Src-driven proliferation. Thus, prior to the loss of cell-cell and cell-matrix adhesiveness, adhesion integrity by P-cadherin at AJs and FAK at FAs could represent a critical step enabling premalignant cells to gain a proliferative advantage.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"226 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2027-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149244784","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":"Fluorescent glutamate reporter mouse line reveals slow stochastic release from rod photoreceptor cells.","authors":"Lou E Townsend, Kwadwo O Boateng, Christopher D Conrady, Channabasavaiah B Gurumurthy, Wallace B Thoreson","doi":"10.1085/jgp.202614045","DOIUrl":"https://doi.org/10.1085/jgp.202614045","url":null,"abstract":"<p><p>The ability to see dim light in darkness requires that second-order rod bipolar cells distinguish small changes in the ongoing release of glutamate-filled vesicles from rods. This task can be facilitated by rapid release, and previous estimates of rod release rates range up to 100 vesicles/s/ribbon. To measure rates and patterns of release, we engineered mice to express a bright fluorescent glutamate reporter (iGluSnFR3.v857.GPI) in rod photoreceptor cells. After validating expression, we measured glutamate release from rods under mesopic and photopic conditions. Under mesopic conditions produced by 900-nm two-photon excitation, light flashes decreased iGluSnFR3 fluorescence consistent with diminished release. Release measured during a chirp light stimulus showed low-pass-frequency characteristics, declining in power from 1 to 10 Hz. To identify single-vesicle events, we loaded iGluSnFR3-expressing rods with dextran-conjugated pHrodo or FM4-64. Brief increases in iGluSnFR3 fluorescence due to vesicle release were accompanied by simultaneous decreases in pHrodo or FM4-64 fluorescence. Tonic release measured from changes in iGluSnFR3 fluorescence occurred stochastically at rates of 20-40 vesicles/s/ribbon under both mesopic and photopic conditions. Capacitance measurements of release from rods voltage-clamped at -40-mV rods suggested a similar rate of 38 vesicles/s/ribbon. The ability of rods to maintain similar release rates over a wide range of background intensities ensures that properties of light adaptation that arise in rods are faithfully transmitted to downstream neurons. This mouse model provides a useful tool for deciphering mechanisms by which light information is transformed at the first synapse in the retina.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"159 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2027-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149344779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unsolved problems with ENaC: From molecules to mammals.","authors":"Lawrence G Palmer","doi":"10.1085/jgp.202614077","DOIUrl":"https://doi.org/10.1085/jgp.202614077","url":null,"abstract":"<p><p>The epithelial Na channel (ENaC) mediates transport of Na+ in the kidney, the colon, the lung, and the sweat and salivary ducts. The activity of these channels is highly regulated and contributes to the maintenance of total body Na+, extracellular fluid volume, and plasma K+. Defects in the channel itself or in its regulation are implicated in hypertension and in other diseases. Despite progress in revealing many aspects of ENaC biology, many important questions remain unanswered. These include the following: What determines the remarkable ion selectivity of the channel? How is the channel directed to the apical plasma membrane? How does aldosterone regulate the channel? What is its role in producing urine with minimal Na+? And to what extent does the channel contribute to essential hypertension, cystic fibrosis, nephrotic syndrome, and liver failure? Here, I will discuss these questions and how they relate to our current understanding of the roles of ENaC in health and disease.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"159 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2027-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149327596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ups and downs of human UNC93B1: Autoimmune and viral conditions.","authors":"Elina Idiiatullina, Jean-Laurent Casanova, Shen-Ying Zhang","doi":"10.70962/jhi.20260059","DOIUrl":"10.70962/jhi.20260059","url":null,"abstract":"<p><p>Mouse Unc93b1 was identified in 2006 by forward genetics as an ER membrane protein essential for the activity of the endosomal nucleic acid-sensing receptors TLR3, TLR7, and TLR9. In vitro studies in mouse and human cells have revealed its cellular functions, including ER-based stabilization and trafficking of endosomal TLR proteins (TLR3, TLR7, TLR8, and TLR9) and regulation of signaling thresholds through competitive trafficking control (TLR7 and TLR9). Human genetic studies have clarified the physiological role of UNC93B1 in natural conditions. Biallelic loss-of-function UNC93B1 mutations impair TLR3 signaling in central nervous system-resident cells, thereby conferring a predisposition to HSV-1 encephalitis. UNC93B1 deficiency may also predispose to other viral infections, as suggested by patients with inherited TLR3 or TLR7 deficiency. Conversely, monoallelic or biallelic UNC93B1 gain-of-function variants enhancing TLR7 and/or TLR8 signaling predispose patients to autoimmunity and inflammation, including early-onset systemic lupus erythematosus and chilblain lupus. Thus, in humans, UNC93B1 maintains a delicate balance between host defense and tolerance to self.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2027-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13682336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149229856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolutionarily diverged on-switch for actin assembly in fungal endocytosis.","authors":"Juliette Sebellin, Fabina Binth Kandiyoth, V T Bagyashree, Andrea Picco, Nicolas Carvalho, Markku Hakala, Anne-Sophie Rivier-Cordey, Alphée Michelot, Christopher P Toret, Marko Kaksonen","doi":"10.1083/jcb.202506135","DOIUrl":"10.1083/jcb.202506135","url":null,"abstract":"<p><p>Clathrin-mediated endocytosis is a conserved eukaryotic trafficking process where an Arp2/3 complex-nucleated branched actin network provides force for vesicle formation. The mechanisms that initiate endocytic actin assembly are incompletely understood. In the fission yeast, Schizosaccharomyces pombe, actin assembly is initiated by Dip1, an Arp2/3 complex activator. In the budding yeast, Saccharomyces cerevisiae, the initiation of actin assembly has remained a mystery. Here, we show that S. cerevisiae Ldb17, the homolog of Dip1, functions as an on-switch for endocytic actin assembly. Unexpectedly, the regulation of Ldb17 is more complicated than that of constitutively active Dip1. Ldb17 is controlled by a coat protein, Sla1, via separate recruitment and activation steps. This regulation was likely lost in the S. pombe lineage, and this simplification may be related to other changes in actin assembly between these species. Our findings add a key missing piece in the understanding of endocytosis in S. cerevisiae and reveal an intriguing evolutionary tinkering of the actin on-switch.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"226 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2027-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13715591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149286987","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}

{"title":"ALMS1 stabilizes the proximal centriole to drive transition zone assembly and ciliogenesis.","authors":"Thao P Phan, Camille Derderian, Vicente Herranz-Pérez, Kathy H Li, Alma L Burlingame, Jeremy F Reiter","doi":"10.1083/jcb.202605019","DOIUrl":"https://doi.org/10.1083/jcb.202605019","url":null,"abstract":"<p><p>The human ciliopathy Alström syndrome is caused by mutations in ALMS1. How ALMS1 contributes to cilia function has been unclear. Unlike other ciliopathy-associated proteins, ALMS1 localizes to the proximal end of centrioles, raising the possibility that it contributes to cilia function via a distinct mechanism. We found that, without ALMS1, centrioles are short and frequently break at their proximal ends. Truncated, broken ALMS1 mutant centrioles display reduced microtubule-organizing activity and disrupted centriole linkers. Without ALMS1, Golgi-derived cargos, including transmembrane components of the transition zone, are impaired in their trafficking to the centrosome. Consequently, ALMS1 is important for transition zone assembly, ciliogenesis, and the control of ciliary membrane composition. In mice, disruption of ALMS1 causes progressive, age-dependent loss of cilia in tissues affected in Alström syndrome, including retina, kidney, and brain. We conclude that Alström syndrome is caused by disruption of proximal centriole integrity and centrosome-directed protein trafficking, compromising ciliary assembly and maintenance.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"226 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2027-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149321559","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":"DOCK2 deficiency due to a novel cryptic splice site mutation.","authors":"Manisha Ahuja, Ina C D Schim van der Loeff, Helen Griffin, Angela Grainger, Joseph D P Willet, Mary Slatter, Zohreh Nademi, Andrew R Gennery, Andrew J Cant, Su Han Lum, Sophie Hambleton, Karin R Engelhardt","doi":"10.70962/jhi.20260146","DOIUrl":"10.70962/jhi.20260146","url":null,"abstract":"<p><p>Autosomal recessive dedicator of cytokinesis 2 (DOCK2) deficiency causes severe, early-onset bacterial and viral infections. We report three siblings with DOCK2 deficiency due to a novel homozygous synonymous variant that results in cryptic mRNA splicing and absence of wild-type protein.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2027-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13701129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149281053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing hypertension in activated PI3K delta syndrome: Findings from Epic Cosmos.","authors":"Brianna Santiago, Jennifer Keelin, Xiaoqi Sun, Christopher Chang","doi":"10.70962/jhi.20250263","DOIUrl":"10.70962/jhi.20250263","url":null,"abstract":"<p><p>APDS is a rare inborn error of immunity with comorbidity patterns that have yet to be characterized at a large scale. Using Epic Cosmos, a de-identified electronic health record database, we conducted a retrospective, cross-sectional analysis of 866 patients identified by structured diagnosis codes (ICD-10: D84.81; SNOMED: 793412000). Findings revealed that hypertension was coded as affecting 28.5% of the cohort, with age-stratified analyses demonstrating higher prevalence among younger APDS patients compared with age-matched non-APDS peers. Among patients aged ≤50 years, hypertension prevalence was 24.05% in the APDS group compared with 10.89% in the age-matched non-APDS population (prevalence ratio 2.21, 95% CI, 1.90-2.57, P < 0.0001). This association remained prominent in a more specific APDS sensitivity cohort in which the base population required an APDS diagnosis, alongside an allergy and immunology encounter. The findings of this paper provide large-scale characterization of APDS and identify hypertension, particularly among younger APDS patients, as a potentially underrecognized comorbidity that warrants further investigation.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2027-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13701131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149281135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MHC-II deficiency in a large Algerian cohort: Clinical, immunological, and genetic characterization.","authors":"Lydia Lamara Mahammed, Brahim Belaid, Koon-Wing Chan, Aida Mohand-Oussaid, Ouardia Drali, Abdelhak Dehimi, Daniel Leung, Lilya Meriem Berkani, Hassiba Sakhri, Asmaa Abed, Meriem Tahir, Fatma Merah, Amina Salmi, Wassila Messadi, Souhila Melzi, Jing Yang, Xing Tian Yang, Jennifer Stoddard, Julie Niemela, Heather Kenney, Fella Dahmoune, Fairouz Guerrouche, Ahlem Mechali, Amina Saad Djaballah, Lamia Amirat, Meriem Oussalah, Yacine Inouri, Saadeddine Dib, Fatima Benbida, Chahynez Boubidi, Hind Ismahen Titri, Lynda Sekfali, Sidi Mohamed Azzouz, Amel Laredj, Fadela Bendaoud, Halima Zerguine, Djohra Hadef, Ahmed Kadi, Djazia Elhadef, Hamza Boucenna, Khadidja Benallal, Moufida Djalab, Chahrazed El Mezouar, Rachid Bouhdjila, Mimouna Bessahraoui, Nadia Bensaadi, Farih Mehdid, Malek Benakli, Farida Harieche, Rawda Aboura, Zoulikha Zeroual, Leila Smati, Salih Bendeddouche, Reda Belbouab, Azzeddine Mekki, Belkacem Bioud, Samir Mohamed Ladj, Merzak Gharnaout, Asmahane Ladjouze, Ourida Gacem, Nafissa Benhalla, Jaime Sou Rosa Duque, Sergio Rosenzweig, Luigi Daniele Notarangelo, Yu Lung Lau, Reda Djidjik","doi":"10.70962/jhi.20260162","DOIUrl":"10.70962/jhi.20260162","url":null,"abstract":"<p><p>MHC class II (MHC-II) deficiency is a rare inborn error of immunity caused by defects in transcriptional regulators of MHC-II expression. In this study, we characterized the clinical, immunological, and molecular features of 107 patients from 98 unrelated Algerian families. Median ages at symptom onset and diagnosis were 5 and 14 mo, respectively, with pneumonia (82%) and chronic diarrhea (73%) predominating. CD4+ T cell lymphopenia occurred in 87.6% and naïve CD4+ T cell depletion in 86.0%. Among 99 genetically characterized patients, variants were identified exclusively in RFXANK (77.8%) and RFXAP (22.2%), including two predominant mutations (RFXANK c.338-25_338del and RFXAP c.368del) and four novel variants. Exploratory comparisons suggested a more severe phenotype in patients carrying RFXAP c.368del than in those carrying RFXANK c.338-25_338del. Five of seven transplanted patients survived versus 33.3% of non-transplanted patients. As the largest MHC-II deficiency cohort reported to date, this study substantially expands current knowledge of the disease and supports targeted genetic diagnosis in North African populations.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2027-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13721797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149303623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental elimination of electrical synapses by UNC-51/UNC-76-mediated vesicular transport.","authors":"Hao Huang, Yuzhi Yang, Yuanhao Xu, Yuli Jian, Shujie Qiu, Zihao Zhao, Dong Yan, Lingfeng Meng","doi":"10.1083/jcb.202602115","DOIUrl":"10.1083/jcb.202602115","url":null,"abstract":"<p><p>Neural circuit maturation requires precise elimination of transient synaptic connections, but how electrical synapses are eliminated remains unknown. Using Caenorhabditis elegans PLM mechanosensory neurons, we found that gap junctions form transiently during early development and are subsequently eliminated as the circuit matures. These transient electrical synapses drive high-frequency calcium oscillations; optogenetic ablation of early gap junctions abolishes calcium dynamics and disrupts chemical synapse formation, while restoring calcium activity independently of gap junction coupling substantially rescues this defect, directly linking electrical synapse-driven calcium dynamics to chemical synapse formation. Through forward genetic screening, we identified the conserved kinase UNC-51/ULK as essential for elimination. UNC-51 phosphorylates the kinesin adaptor UNC-76/FEZ to promote RAB-10-dependent net retrograde removal of innexins, progressively depleting innexin proteins from the synaptic site. Disrupting this pathway prevents elimination, causing persistent electrical synapses and neuronal hyperactivity. These findings establish a conserved framework for developmental elimination of functionally essential transient electrical connectivity.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"226 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2027-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13741927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149342324","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}