Journal of Clinical Investigation最新文献

{"title":"Marburg virus glycoprotein mRNA vaccine is more protective than a virus-like particle-forming mRNA vaccine.","authors":"Chandru Subramani, Michelle Meyer, Matthew A Hyde, Margaret E Comeaux, Haiping Hao, James E Crowe, Vsevolod L Popov, Harshwardhan Thaker, Sunny Himansu, Andrea Carfi, Alexander Bukreyev","doi":"10.1172/JCI194586","DOIUrl":"10.1172/JCI194586","url":null,"abstract":"<p><p>Although virus-like particle (VLP) vaccines were shown to be effective against several viruses, their advantage over vaccines that include envelope protein only is not completely clear, particularly for mRNA-encoded VLPs. We conducted a side-by-side comparison of the immunogenicity and protective efficacy of mRNA vaccines encoding the Marburg virus (MARV) full-length glycoprotein (GP) delivered alone or as a VLP. Electron microscopy confirmed VLP formation when MARV GP and matrix protein VP40 were coexpressed. We vaccinated guinea pigs with a 2-component mRNA vaccine encoding GP and VP40 (VLP) or GP alone. At the highest dose, both vaccines protected fully, although the VLP vaccine elicited a slightly lower humoral response than did the GP-only mRNA vaccine. However, at low doses, GP-only mRNA conferred 100% protection, whereas the VLP vaccine conferred only partial protection. In mice, VLP mRNA induced a moderate preference for GP-specific CD8+ T cell responses, whereas the GP-only mRNA somewhat favored CD4+ T cell responses. Guinea pig whole-blood RNA-Seq revealed that the VLP vaccine downregulated genes associated with various biological and metabolic processes, including the NF-κB signaling pathway, whereas the GP-only vaccine upregulated IFN signaling. Overall, the VLP mRNA vaccine was less immunogenic and protective, whereas the GP-only mRNA vaccine conferred robust protection with a dose of as little as 1 μg in guinea pigs.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutations in the spliceosomal gene SNW1 cause neurodevelopment disorders with microcephaly.","authors":"Lei Ji, Jin Yan, Nicole A Losurdo, Hua Wang, Liangjie Liu, Keyi Li, Zhen Liu, Zhenming Guo, Jing Xu, Adriana Bibo, Decheng Ren, Ke Yang, Yingying Luo, Fengping Yang, Gui Wang, Zhenglong Xiang, Yuan Wang, Huaizhe Zhan, Hu Pan, Juanli Hu, Jianmin Zhong, Rami Abou Jamra, Pia Zacher, Luciana Musante, Flavio Faletra, Paola Costa, Caterina Zanus, Nathalie Couque, Lyse Ruaud, Anna M Cueto-González, Hector San Nicolas Fernández, Eduardo Tizzano, Nuria Martinez Gil, Xiaorong Liu, Weiping Liao, Layal Abi Farraj, Alden Y Huang, Liying Zhang, Aparna Murali, Esther Schmuel, Christina S Han, Kayla King, Weiyue Gu, Pengchao Wang, Kai Li, Nichole Link, Guang He, Shan Bian, Xiao Mao","doi":"10.1172/JCI186119","DOIUrl":"10.1172/JCI186119","url":null,"abstract":"<p><p>The spliceosome is a critical cellular machinery responsible for pre-mRNA splicing that is essential for the proper expression of genes. Mutations in its core components are increasingly linked to neurodevelopmental disorders, such as primary microcephaly. Here, we investigated the role of SNW domain-containing protein 1 (SNW1), a spliceosomal protein, in splicing integrity and neurodevelopment. We identified 9 heterozygous mutations in the SNW1 gene in patients presenting with primary microcephaly. These mutations impaired SNW1's interactions with core spliceosomal proteins, leading to defective RNA splicing and reduced protein functionality. Using Drosophila melanogaster and human embryonic stem cell-derived cerebral organoids models, we demonstrated that SNW1 depletion resulted in significant reductions in neural stem cell proliferation and increased apoptosis. RNA-Seq revealed disrupted alternative splicing, especially skipping exons, and altered expression of neurodevelopment-associated genes (CENPE, MEF2C, and NRXN2). Our findings provide crucial insights into the molecular mechanisms by which SNW1 dysfunction contributes to neurodevelopmental disorders and underscore the importance of proper spliceosome function in brain development.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blood-storage duration affects hematological and metabolic profiles in patients with sickle cell disease receiving transfusions.","authors":"Matthew S Karafin, Abby L Grier, Ross M Fasano, Anton Ilich, David Wichlan, Ada Chang, Sonjile M James, Hailly E Butler, Oleg Kolupaev, Melissa C Caughey, Daniel J Stephenson, Julie A Reisz, Nigel S Key, Joshua J Field, Jane A Little, Steven L Spitalnik, Angelo D'Alessandro","doi":"10.1172/JCI192920","DOIUrl":"10.1172/JCI192920","url":null,"abstract":"<p><p>BACKGROUNDPatients with sickle cell disease (SCD) frequently receive RBC units stored near the end of their permissible storage duration. We aimed to determine whether RBC storage duration influences recipient hematological, metabolic, and clinical chemistry parameters.METHODSIn a randomized, prospective, double-blind trial, 24 adults with SCD receiving chronic transfusion therapy were assigned to receive three consecutive outpatient transfusions with RBCs stored for either ≤10 days (short-stored; n = 13) or ≥30 days (long-stored; n = 11). Blood samples were collected from transfused units and from recipients at predefined time points for metabolomics, cytokine, and clinical laboratory analyses. The primary outcomes included post-transfusion hemoglobin and RBC count increments, metabolic markers of oxidative stress, iron metabolism, inflammation, and renal function.RESULTSTransfusion of short-stored RBCs was associated with significantly higher circulating 2,3-bisphosphoglycerate levels for up to 2 weeks after transfusion. Nadir RBC counts and hemoglobin A levels were higher in recipients of short-stored RBCs. In contrast, recipients of long-stored RBCs had higher transferrin saturation and plasma iron levels, elevated markers of oxidative stress and renal dysfunction, and increased proinflammatory cytokines and immunomodulatory metabolites. Metabolomics revealed storage age-dependent alterations in glycolysis, purine, and sphingolipid metabolism. Cytokine profiles and hematologic parameters corroborated the metabolic findings, indicating improved post-transfusion metabolic and inflammatory status with short-stored RBCs.CONCLUSIONTransfusion of short-stored RBCs yielded favorable metabolic and hematologic outcomes in adults with SCD, independent of immediate clinical endpoints.TRIAL REGISTRATIONClinicalTrials.gov NCT03704922FUNDINGNational Heart, Lung, and Blood Institute (NHLBI), NIH (K23HL136787, R01HL148151, R01HL146442, and R01HL149714).</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revealing hyperactivated IFN-γ pathways in perianal fistulizing Crohn's disease using single-cell and spatial multi-omics.","authors":"Siyan Cao, Khai M Nguyen, Kaiming Ma, Tingyi Tan, Xin Yao, Ta-Chiang Liu, Malek Ayoub, Jalpa Devi, Sami Samaan, Yizhou Liu, Radhika Smith, Matthew L Silviera, Steven R Hunt, Paul E Wise, Matthew G Mutch, Sean C Glasgow, William C Chapman, Michelle L Cowan, Matthew A Ciorba, Marco Colonna, Parakkal Deepak","doi":"10.1172/JCI193413","DOIUrl":"10.1172/JCI193413","url":null,"abstract":"<p><p>Up to 40% patients with Crohn's disease suffer from perianal disease, a debilitating complication with unclear etiology. This study identified unique pathophysiology which may help develop novel therapies.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404762/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuropilin-2 functions as a coinhibitory receptor to regulate antigen-induced inflammation and allograft rejection.","authors":"Johannes Wedel, Nora Kochupurakkal, Sek Won Kong, Sayantan Bose, Ji-Won Lee, Madeline Maslyar, Bayan Alsairafi, Kayla MacLeod, Kaifeng Liu, Hengcheng Zhang, Masaki Komatsu, Hironao Nakayama, Diane R Bielenberg, David M Briscoe","doi":"10.1172/JCI172218","DOIUrl":"10.1172/JCI172218","url":null,"abstract":"<p><p>Coinhibitory receptors function as central modulators of the immune response to resolve T effector activation and/or to sustain immune homeostasis. Here, using humanized SCID mice, we found that neuropilin-2 (NRP2) is inducible on late effector and exhausted subsets of human CD4+ T cells and that it is coexpressed with established coinhibitory molecules including PD-1, CTLA4, TIGIT, LAG3, and TIM3. In murine models, we also found that NRP2 is expressed on effector memory CD4+ T cells with an exhausted phenotype and that it functions as a key coinhibitory molecule. Knockout (KO) of NRP2 resulted in hyperactive CD4+ T cell responses and enhanced inflammation in delayed-type hypersensitivity and transplantation models. After cardiac transplantation, allograft rejection and graft failure were accelerated in global as well as CD4+ T cell-specific KO recipients, and enhanced alloimmunity was dependent on NRP2 expression on CD4+ T effectors but not on CD4+Foxp3+ Tregs. Also, KO Tregs were found to be as efficient as WT cells in the suppression of effector responses in vitro and in vivo. These collective findings identify NRP2 as a potentially novel coinhibitory receptor and demonstrate that its expression on CD4+ T effector cells is of great functional importance in immunity.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 13","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms.","authors":"Milan Stoiljkovic, Jae Eun Song, Hee-Kyung Hong, Heiko Endle, Luis Varela, Jonatas Catarino, Xiao-Bing Gao, Zong-Wu Liu, Peter Sotonyi, Sabrina Diano, Jonathan Cedernaes, Joseph Bass, Tamas L Horvath","doi":"10.1172/JCI185000","DOIUrl":"10.1172/JCI185000","url":null,"abstract":"<p><p>Sustaining the strong rhythmic interactions between cellular adaptations and environmental cues has been posited as essential for preserving the physiological and behavioral alignment of an organism to the proper phase of the daily light/dark (LD) cycle. Here, we demonstrate that mitochondria and synaptic input organization of suprachiasmatic (SCN) vasoactive intestinal peptide-expressing (VIP-expressing) neurons showed circadian rhythmicity. Perturbed mitochondrial dynamics achieved by conditional ablation of the fusogenic protein mitofusin 2 (Mfn2) in VIP neurons caused disrupted circadian oscillation in mitochondria and synapses in SCN VIP neurons, leading to desynchronization of entrainment to the LD cycle in Mfn2-deficient mice that resulted in an advanced phase angle of their locomotor activity onset, alterations in core body temperature, and sleep-wake amount and architecture. Our data provide direct evidence of circadian SCN clock machinery dependence on high-performance, Mfn2-regulated mitochondrial dynamics in VIP neurons for maintaining the coherence in daily biological rhythms of the mammalian organism.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 13","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The human glucocorticoid receptor variant rs6190 increases blood cholesterol and promotes atherosclerosis.","authors":"Hima Bindu Durumutla, April Haller, Greta Noble, Ashok Daniel Prabakaran, Kevin McFarland, Hannah Latimer, Akanksha Rajput, Olukunle Akinborewa, Bahram Namjou-Khales, David Y Hui, Mattia Quattrocelli","doi":"10.1172/JCI190180","DOIUrl":"10.1172/JCI190180","url":null,"abstract":"<p><p>Elevated cholesterol poses cardiovascular risks. The glucocorticoid receptor (GR) harbors a still undefined role in cholesterol regulation. Here, we report that a coding SNP in the gene encoding the GR, rs6190, is associated with increased cholesterol in women according to UK Biobank and All of Us (NIH) datasets. In SNP-genocopying mice, we found that the SNP enhanced hepatic GR activity to transactivate Pcsk9 and Bhlhe40, negative regulators of LDL and HDL receptors, respectively. In mice, the SNP was sufficient to elevate circulating cholesterol across all lipoprotein fractions and the risk and severity of atherosclerotic lesions on the proatherogenic hAPOE*2/*2 background. The SNP effect on atherosclerosis was blocked by in vivo liver knockdown of Pcsk9 and Bhlhe40. Also, corticosterone and testosterone were protective against the mutant GR program in cholesterol and atherosclerosis in male mice, while the SNP effect was additive to estrogen loss in females. Remarkably, we found that the mutant GR program was conserved in human hepatocyte-like cells using CRISPR-engineered, SNP-genocopying human induced pluripotent stem cells. Taken together, our study leverages a nonrare human variant to uncover a GR-dependent mechanism contributing to atherogenic risk, particularly in women.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamics of Th1/Th17 responses and antimicrobial pathways in leprosy skin lesions.","authors":"Priscila R Andrade, Feiyang Ma, Jing Lu, Jaime de Anda, Ernest Y Lee, George W Agak, Craig J Dobry, Bruno J de Andrade Silva, Rosane Mb Teles, Lilah A Mansky, Jonathan Perrie, Dennis J Montoya, Bryan D Bryson, Johann E Gudjonsson, Gerard Cl Wong, Euzenir N Sarno, Matteo Pellegrini, Robert L Modlin","doi":"10.1172/JCI190736","DOIUrl":"10.1172/JCI190736","url":null,"abstract":"<p><p>BACKGROUNDReversal reactions (RRs) in leprosy are acute immune episodes marked by inflammation and bacterial clearance, offering a model to study the dynamics of host responses to Mycobacterium leprae. These episodes are often severe and difficult to treat, frequently progressing to permanent disabilities. We aimed to characterize the immune mechanisms and identify antimicrobial effectors during RRs.METHODSWe performed RNA-Seq on paired skin biopsy specimens collected from 9 patients with leprosy before and at RR diagnosis, followed by differential gene expression and functional analysis. A machine-learning classifier was applied to predict membrane-permeabilizing proteins. Antimicrobial activity was assessed in M. leprae-infected macrophages and axenic cultures.RESULTSIn the paired pre-RR and RR biopsy specimens, a 64-gene antimicrobial response signature was upregulated during RR and correlated with reduced M. leprae burden. Predicted upstream regulators included IL-1β, TNF, IFN-γ, and IL-17, indicating activation of both the Th1 and Th17 pathways. A machine-learning classifier identified 28 genes with predicted membrane-permeabilizing antimicrobial activity, including S100A8. Four proteins (S100A7, S100A8, CCL17, and CCL19) demonstrated antimicrobial activity against M. leprae in vitro. Scanning electron microscopy revealed membrane damage in bacteria exposed to these proteins.CONCLUSIONRR is associated with a robust antimicrobial gene program regulated by Th1 and Th17 cytokines. We identified potentially novel host antimicrobial effectors that showed activity against M. leprae, suggesting potential strategies to bolster Th1 and Th17 responses for combating intracellular mycobacterial infections.FUNDINGNIH grants R01 AI022553, R01 AR040312, R01 AR073252, R01 AI166313, R01 AI169526, P50 AR080594, and 4R37 AI052453-21 and National Science Foundation (NSF) grant DMR2325840.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activated STING in the thymic epithelium alters T cell development and selection leading to autoimmunity.","authors":"Zimu Deng, Christopher S Law, Santosh Kurra, Noa Simchoni, Anthony K Shum","doi":"10.1172/JCI180252","DOIUrl":"10.1172/JCI180252","url":null,"abstract":"<p><p>Coatomer protein complex subunit α (COPA) syndrome is a monogenic disorder of immune dysregulation that leads to interstitial lung disease and high-titer autoantibodies. Constitutive activation of the innate immune molecule stimulator of interferon genes (STING) is centrally involved in disease. However, the mechanisms by which STING results in autoimmunity are not well understood in COPA syndrome and other STING-associated diseases. Prior studies showed a cell autonomous role for STING in thymocyte development. Single-cell data of human thymus demonstrated that STING is highly expressed in medullary thymic epithelial cells (mTECs) and at levels much greater than in T cells. Here, we show that in certain contexts, activated STING exerts a functional role in the thymic epithelium to alter thymocyte selection and predisposes to autoimmunity. In CopaE241K/+ mice, activated STING in mTECs amplified IFN signaling, impaired macroautophagy, and caused a defect in negative selection of T cell precursors. WT mice given a systemic STING agonist phenocopied the selection defect and showed enhanced thymic escape of a T cell clone targeting a self-antigen also expressed in melanoma. Our work demonstrates that STING activation in TECs shapes the T cell repertoire and contributes to autoimmunity, findings that are important for conditions that activate thymic STING.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The E3 ubiquitin ligase Cul5 regulates hematopoietic stem cell function for steady-state hematopoiesis in mice.","authors":"Siera A Tomishima, Dale D Kim, Nadia Porter, Ipsita Guha, Asif A Dar, Yohaniz Ortega-Burgos, Jennifer Roof, Hossein Fazelinia, Lynn A Spruce, Christopher S Thom, Robert L Bowman, Paula M Oliver","doi":"10.1172/JCI180913","DOIUrl":"10.1172/JCI180913","url":null,"abstract":"<p><p>The balance of hematopoietic stem cell (HSC) self-renewal versus differentiation is essential to ensure long-term repopulation capacity while allowing response to events that require increased hematopoietic output. Proliferation and differentiation of HSCs and their progeny are controlled by the JAK/STAT pathway downstream of cytokine signaling. E3 ubiquitin ligases, like Cullin 5 (CUL5), can regulate JAK/STAT signaling by degrading signaling intermediates. Here we report that mice lacking CUL5 in hematopoietic cells (Cul5Vav-Cre) have increased numbers of hematopoietic stem and progenitor cells (HSPCs), splenomegaly, and extramedullary hematopoiesis. Differentiation in Cul5Vav-Cre mice is myeloid- and megakaryocyte-biased, resulting in leukocytosis, anemia, and thrombocytosis. Cul5Vav-Cre mice had increased HSC proliferation and circulation, associated with a decrease in CXCR4 surface expression. In bone marrow cells, we identified LRRC41 coimmunoprecipitated with CUL5, and vice versa, supporting that CRL5 forms a complex with LRRC41. We identified an accumulation of LRRC41 and STAT5 in Cul5Vav-Cre HSCs during IL-3 stimulation, supporting their regulation by CUL5. Whole-cell proteome analysis of HSPCs from Cul5Vav-Cre bone marrow identified upregulation of many STAT5 target genes and associated pathways. Finally, JAK1/2 inhibition with ruxolitinib normalized hematopoiesis in Cul5Vav-Cre mice. These studies demonstrate the function of CUL5 in HSC function, stem cell fate decisions, and regulation of IL-3 signaling.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}