JCI insight最新文献

{"title":"Keratinocyte VISTA attenuates UV light-induced skin injury by suppressing cutaneous type I interferon (IFN-I) response.","authors":"Zachary T Peters, Lindsay K Mendyka, J'Voughnn A Blake, Himanshu B Goswami, Angelique N Cortez, Grace E Crossland, Sicong Shan, Elizabeth C Nowak, Myana Keusch, Mrinal K Sarkar, Johann E Gudjonsson, Christopher M Burns, Dorothea T Barton, Bruce R Blazar, Tyler J Curiel, Rodwell Mabaera, Victoria P Werth, Andrea Kalus, Keith B Elkon, Randolph J Noelle, Sladjana Skopelja-Gardner","doi":"10.1172/jci.insight.200540","DOIUrl":"10.1172/jci.insight.200540","url":null,"abstract":"<p><p>Persistent production of type I interferons (IFN-Is) is a hallmark of cutaneous lupus erythematosus (CLE). Ultraviolet (UV) light stimulates IFN-I response in the skin and exacerbates CLE. Here, we identify V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) as a negative regulator of both basal and UV-induced IFN-I response in the skin and show that VISTA limits skin photosensitivity in an IFN-I-dependent manner, in part through Stimulator of Interferon Genes (STING). Furthermore, we demonstrate a novel role for VISTA in keratinocytes both at steady state and in response to UV light. Conditional deletion of VISTA in epidermal keratinocytes results in a ~10-fold increase in basal skin IFN-I scores and a heightened UV-induced skin injury score, both of which are dependent on IFN-I signaling. VISTA-targeting monoclonal antibodies suppress the UV-induced IFN-I response in human keratinocytes and in mice expressing human VISTA in vivo, thereby reducing UV-induced skin injury scores. Together, these findings identify VISTA as a keratinocyte-intrinsic checkpoint that restrains STING-associated IFN-I response in the skin and suggest VISTA agonism as a therapeutic strategy to limit photosensitivity in CLE.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109837","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":"Targeting HSPA1A with geranylgeranylacetone alleviates ADTKD-UMOD via suppression of endoplasmic reticulum stress and ferroptosis.","authors":"Wen Shi, Yan Yang, Xianli Wen, Qianqian Wu, Jinxuan Wei, Xin-Lu Wang, Junyuan Shen, Siqi Peng, Xiaoliang Zhang, Bi-Cheng Liu, Bin Wang","doi":"10.1172/jci.insight.207210","DOIUrl":"https://doi.org/10.1172/jci.insight.207210","url":null,"abstract":"<p><p>Missense mutations in the UMOD gene are a well-established genetic cause of autosomal dominant tubulointerstitial kidney disease (ADTKD). Here, we report two ADTKD pedigrees carrying de novo UMOD mutations, p.His36Tyr (H36Y) and p.Trp31Cys (W31C). To elucidate the underlying pathogenic mechanisms and explore targeted therapeutic strategies, we generated a UMODH36Y/+ knock-in mouse model using CRISPR/Cas9 technology, which recapitulated the major clinical manifestations observed in patients. Through single-cell RNA sequencing and experimental validation, we demonstrated that uromodulin mutations triggered endoplasmic reticulum (ER) stress and the unfolded protein response, with ferroptosis identified as the predominant mode of cell death in this disease. These findings were further confirmed in plasmid-transfected cell models expressing UMODH36Y and UMODW31C. Moreover, the molecular chaperone HSPA1A was identified as a potential therapeutic target. Geranylgeranylacetone, targeting HSPA1A as a chaperone drug, effectively mitigated endoplasmic reticulum stress, alleviated ferroptosis, and delayed the progression of renal dysfunction. Based on novel uromodulin mutations, our study reveals a pathogenic ER-ferroptosis axis in ADTKD-UMOD, deepens the insight into the pathogenesis of ADTKD-UMOD, and provides a promising strategy for developing chaperone therapy with drug repurposing in genetic kidney diseases.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109919","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":"Anti-Notch plus endocrine therapy in ER+ breast cancer inhibits cancer stem cells by increasing DAXX.","authors":"Kathy S Albain, Debra Wyatt, Andrei Zlobin, Susan G Hilsenbeck, Cheryl M Czerlanis, Daniel S Peiffer, Kyle R Convington, Constantine Godellas, Shelly S Lo, Patricia A Robinson, Kathy Czaplicki, Barbara Busby, Davide Bova, Ping Tang, Patrick J Stiff, Suzanne Aw Fuqua, Lucio Miele, Clodia Osipo","doi":"10.1172/jci.insight.172506","DOIUrl":"https://doi.org/10.1172/jci.insight.172506","url":null,"abstract":"<p><p>Resistance to endocrine therapy (ET) in ER+ breast cancer is mediated by Notch signaling, but the clinical application of anti-Notch therapy has been limited by the lack of predictive biomarkers. To identify Notch-regulated biomarkers, we conducted a pre-surgical window study evaluating ET combined with the γ-secretase inhibitor (GSI) MK-0752. RNA expressions in tumors were measured using an Affymetrix array and by real-time PCR. ET plus GSI showed more genes were decreased than ET alone. Specifically, DAXX, NOXA, and LFNG RNAs were increased, while fifteen additional transcripts were decreased. Mechanistically, GSI reduced Notch1 occupancy at CSL-binding elements within HES1, HEY2, HEYL, CCND1, MKI67, and DAXX genes, and inhibited cancer stem cells (CSCs) by 90% to 100%. This anti-CSC effect required DAXX, while GSI treatment or Notch1/4 knockdown increased DAXX expression, suggesting transcriptional repression by Notch. Using mouse tumor xenograft studies, ET plus MK-0752 resulted in complete regression of MCF-7 tumors, with DAXX-high tumors showing greater treatment sensitivity. Clinically, high DAXX expression was associated with improved recurrence-free and overall survival. This study found that anti-Notch plus ET in ER+ breast cancer inhibits cancer stem cells by increasing DAXX, a promising predictive biomarker. These findings support clinical evaluation of therapies that increase DAXX expression.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080875","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":"Whole-genome methylation sequencing uncovers PASC signature elicited by T4 lymphocytes, shared with pulmonary fibrosis risk.","authors":"Andy Madrid, Joseph Balnis, Lisa A Drake, Anupama Tiwari, Vraj J Patel, Paul J Feustel, Jihua Liu, Sündüz Keleş, Fangxiu Xu, Chris L Wright, Alvaro G Hernandez, Recai Yucel, Marc A Judson, Harold A Singer, Reid S Alisch, Ariel Jaitovich","doi":"10.1172/jci.insight.210824","DOIUrl":"10.1172/jci.insight.210824","url":null,"abstract":"<p><strong>Background: </strong>Long-COVID, or post-acute sequelae of COVID-19 (PASC), leads to debilitating physical and cognitive deficits. No PASC molecular signature present in patients with diverse symptoms has been described. While PASC engages pathways regulating pro-fibrotic programs, no comparison of PASC with fibrosis-associated epigenetic landscapes has been reported at the bulk or single-cell level. We hypothesize that a subset of DNA methylation changes are present in PASC patients from multiple cohorts, predominate in specific immune or inflammatory cell-types, and overlap with the epigenetic profile of patients at risk of pulmonary fibrosis.</p><p><strong>Methods: </strong>Two distinct prospective cohorts, in 2021 and in 2022-24, involving 203 patients with PASC underwent bulk whole genome methylation sequencing (WGMS). Single-cell WGMS data was generated from an independent PASC cohort. Sixty-eight pre-pandemic patients with conditions elevating risk of pulmonary fibrosis development were compared with PASC.</p><p><strong>Results: </strong>Sixteen differentially methylated regions distinguished PASC versus multiple independent, healthy controls. Single-cell analysis of these regions indicated trending relative hypermethylation at multiple cell types, with T4 lymphocytes eliciting hypermethylation at most of the sequences identified to be PASC-specific DMRs in the bulk analysis. Patients at risk of pulmonary fibrosis development elicited DNA methylation changes overlapping PASC.</p><p><strong>Conclusion: </strong>In two independent prospective cohorts, blood WGMS identifies differentially methylated regions associated with PASC. Hypermethylation of these regions is predominantly, although not exclusively, associated with T4 lymphocytes and overlap with changes present in pre-pandemic pulmonary fibrosis at-risk patients.</p><p><strong>Funding: </strong>National Institutes of Health award HL160661 (AJ); and AI173035 (AJ and RSA).</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080898","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":"Autoantibody landscapes in Long COVID with neurological symptoms show heterogeneity without a shared disease signature.","authors":"Debanjana Chakravarty, Ravi Dandekar, Vishal D Lashkari, Iris Tilton, Lindsay McAlpine, Jennifer Chiarella, Allison Nelson, Thomas Ngo, PeiXi Chen, Chung-Yu Wang, Aditi Saxena, Bryan Castillo-Rojas, Kelsey Zorn, David R Tribble, Timothy H Burgess, Leah H Rubin, Stephanie A Richard, Brian K Agan, Simon D Pollett, Shelli Farhadian, Serena Spudich, Samuel J Pleasure, Michael R Wilson","doi":"10.1172/jci.insight.207122","DOIUrl":"10.1172/jci.insight.207122","url":null,"abstract":"<p><strong>Background: </strong>Neurological Long COVID (n-LC) includes persistent cognitive and autonomic symptoms after SARS-CoV-2 infection. Prior studies of post-COVID conditions have described diverse humoral autoreactivity. It remains unclear whether n-LC is associated with a consistent CNS-directed humoral signature.</p><p><strong>Methods: </strong>We performed a cross-cohort case-control analysis to detect autoantibodies in cerebrospinal fluid (CSF) and serum from n-LC participants. In the Yale COVID Mind Study cohort, CSF from n-LC participants and pre-pandemic and recovered controls was assessed using mouse brain immunofluorescence and proteome-wide phage immunoprecipitation sequencing (PhIP-Seq), followed by supervised modeling and orthogonal validation assays. In the Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (IDCRP EPICC) cohort, post-COVID sera collected prior to iPhone- or iPad-based cognitive screening were profiled by PhIP-Seq and compared between participants with and without cognitive impairment.</p><p><strong>Results: </strong>CSF immunoreactivity on mouse brain tissue was observed in both n-LC and controls, with similar overall frequencies. PhIP-Seq identified sparse, patient-specific peptide reactivities to nuclear and neuronal proteins in CSF and serum. Supervised models provided limited discrimination between cases and controls. Candidate autoantigens had limited disease specificity on orthogonal testing. EPICC serum autoantibody profiling similarly failed to distinguish individuals with and without cognitive impairment.</p><p><strong>Conclusions: </strong>Across cohorts and compartments, n-LC was not associated with a shared CNS-directed autoantibody signature using the approaches employed. Observed heterogeneity may reflect biological diversity, although limited statistical power to detect a shared response cannot be excluded.</p><p><strong>Funding: </strong>Grants HU00012020067, HU00012120103, HU00011920111, R01NS125693, R01MH125737, and R01AI157488 from the Defense Health Program and NIH.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080927","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":"Spatial N-Glycan Imaging and Machine Learning Classify Hepatocellular Carcinoma and Predict Glutamine Synthetase Status.","authors":"Muhammed F Bayram, Jade K Macdonald, Andrew DelaCourt, Peggi M Angel, Richard R Drake, Aatur Singhi, David Geller, Satdarshan P Monga, Amit Singal, Anand Mehta","doi":"10.1172/jci.insight.209628","DOIUrl":"10.1172/jci.insight.209628","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) exhibits molecular heterogeneity that challenges histopathologic classification and biomarker discovery. We assessed whether spatially resolved N-glycan imaging with machine learning could classify tumor regions and infer glutamine synthetase (GS) status.</p><p><strong>Methods: </strong>In this retrospective study, MALDI mass spectrometry imaging of N-glycans was performed on formalin-fixed, paraffin-embedded sections from two independent cohorts (discovery, n = 88; validation, n = 60) with pathologist annotation. An XGBoost classifier was trained on 90 discriminative N-glycan features using patient-grouped cross-validation. Performance was assessed by AUC for pixel- and biopsy-level discrimination of tumor from adjacent non-tumor tissue, and for GS status classification.</p><p><strong>Results: </strong>Pixel-level AUCs were 0.95 (cross-validation) and 0.89 (external validation); biopsy-level AUCs were 1.0 and 0.97, correctly identifying 97% of tumor-containing biopsies. Probability maps recapitulated pathologist-defined boundaries; UMAP embeddings captured inter- and intratumoral heterogeneity. Discriminative species (m/z 2393.846, 1905.634, 1743.579, 1809.639) reflected complex, fucosylated, branched remodeling. N-glycans bearing six GlcNAc residues were enriched in GS+ (n = 45) versus GS- (n = 17) tumors (P = 0.001) and discriminated GS status (AUC = 0.75), consistent with GLUL and MGAT5 upregulation in TCGA-LIHC.</p><p><strong>Conclusion: </strong>MALDI N-glycan imaging with machine learning enables spatially resolved, objective classification of HCC and links glycan phenotypes to tumor-associated metabolic programs.</p><p><strong>Trial registration: </strong>Not applicable; retrospective analysis of archival, de-identified tissue.</p><p><strong>Funding: </strong>NIH/NCI R01CA285370, 1R01CA289381, R33CA267226, R01CA282022, R21CA263464, R21CA286287, R01CA253460, S10OD030212, R01CA251155, R01CA250227, U01CA271887, P50CA295495, P30CA138313, P20GM130457, P30DK123704, P30DK120531,R24DK139775; NIH/NIA R01AG078702; Smart State Endowment, State of South Carolina; LeDucq Foundation.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080849","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":"Sex-dependent effects of neonatal hyperoxia on prefrontal cortex development.","authors":"Xingrao Ke, Wei Yu, Carl F Schreck, Joseph M Varberg, Melissa A Gener, Daniel A Louiselle, Sheng Xia, Sherry M Mabry, Heather L Menden, Venkatesh Sampath, Robert H Lane, Kaela M Varberg","doi":"10.1172/jci.insight.209805","DOIUrl":"10.1172/jci.insight.209805","url":null,"abstract":"<p><p>Premature infants often require supplemental oxygen therapy, a major risk factor for bronchopulmonary dysplasia and subsequent neurodevelopmental impairment. To determine how neonatal hyperoxia affects prefrontal cortex (PFC) development, we exposed neonatal mice to 85% oxygen (O₂) from postnatal day (P)1-P14 and performed integrated single-nucleus transcriptomic and chromatin accessibility profiling with in vivo and in vitro validation. Hyperoxia induced sex-dependent cellular remodeling, reducing L4/5 intratelencephalic projecting glutamatergic neurons in females and mature oligodendrocytes in males. Across both sexes, hyperoxia suppressed oligodendrocyte maturation, with decreased expression of the myelination genes proteolipid protein 1 (Plp1) and myelin basic protein (Mbp), altered chromatin accessibility, and increased oligodendrocyte transcription factor 2 (OLIG2) protein expression. Regulatory responses were sex specific, with tumor protein p53 (TP53)-regulated metabolic disruption and lysine demethylase 3A (Kdm3a) induction in females, and Netrin-1 signaling in males. Hyperoxia impaired oligodendrocyte progenitor cell (OPC) proliferation and differentiation. These abnormalities were recapitulated in postmortem PFC tissue from infants with BPD and human induced pluripotent stem cell (iPSC)-derived OPCs. These findings show that neonatal hyperoxia disrupts PFC development through sex-dependent effects on neuronal and oligodendrocyte lineages while converging on impaired myelination, highlighting oligodendrocyte dysfunction as a clinically relevant consequence of neonatal oxygen exposure.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080871","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":"Serine palmitoyltransferase (SPT) inhibition in SPTSSA-related complex hereditary spastic paraplegia.","authors":"Yi Gong, Robert Thompson, Ashley M Glover, Kenneth Gable, Sita D Gupta, Natalie Golovanov, Julie Tassinari, Nathan Casey, Brian D Wishart, Elise L Townsend, April Qian, Martin Selig, Armen Yerevanian, Teresa M Dunn, Florian Eichler","doi":"10.1172/jci.insight.206228","DOIUrl":"https://doi.org/10.1172/jci.insight.206228","url":null,"abstract":"<p><p>Defective feedback inhibition of serine palmitoyltransferase (SPT) caused by pathogenic SPTSSA variants underlies childhood-onset complex hereditary spastic paraplegia, yet the developmental timing and therapeutic reversibility of sphingolipid dysregulation remain unclear. We generated a knock-in mouse carrying the disease-associated SptssaT51I variant and show that heterozygous animals exhibit preserved intrinsic SPT activity but impaired ORMDL-mediated regulation, leading to sustained elevation of bioactive sphingolipid intermediates that peak during postnatal myelination. Although gross myelin formation was initially maintained, excess sphingolipid flux rendered oligodendrocytes and neurons selectively vulnerable. Dietary L-serine, which augments SPT substrate availability, amplified sphingolipid accumulation in mutant but not wild-type mice, unmasking progressive spasticity, axonal injury, myelin ultrastructural defects, and, when administered during early postnatal development, severe pulmonary pathology likely responsible for lethality. Pharmacologic SPT inhibition with myriocin normalized sphingolipid synthesis, prevented serine-induced lethality, and reversed neurological and metabolic abnormalities. Translating these findings, treatment of a child with SPTSSA-T51I-associated complex hereditary spastic paraplegia using the FDA approved SPT inhibitor D-Cycloserine resulted in sustained improvement in spasticity, reduced baclofen requirement, and decreased plasma levels of neurofilament light chain (NFL). These data define dysregulated sphingolipid biosynthesis as a developmentally and metabolically sensitive driver of neurodegeneration and suggest SPT inhibition as a mechanistically grounded therapeutic strategy.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080924","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":"The E3 ubiquitin ligase HECTD3 controls immune colonic inflammation by restricting Myd88 activation and signaling.","authors":"Shamima Islam, Shahnewaj Mannan, Ashley Zuniga, Upasana Parthasarathy, Valeriu B Cismasiu, Leonardo Silvane, Sayan Chakraborty, Divya Priyanka Talada, Raghwendra Pratap Singh, Tomas Zelenka, Amreen Naveen, Sephra Chyanne Vickers, Michael Gm Grant, Jonathan J Cho, Theodore Drashansky, Alexander J Kwiatkowski, Xintong Liu, Ross Tomaino, Olga A Guryanova, Mariola J Ferraro, Sang Yong Kim, Christian Jobin, Benjamin G Keselowsky, Hongmin Li, Paulo C Rodriguez, Martina Molgora, Amer A Beg, Timothy I Shaw, Zheng Ruan, Lixin Wan, Dorina Avram","doi":"10.1172/jci.insight.185437","DOIUrl":"https://doi.org/10.1172/jci.insight.185437","url":null,"abstract":"<p><p>Ubiquitination is an important post-translational modification associated with essential cellular processes and implicated in regulation of immunity. Here we show that deletion of the E3 ubiquitin ligase Hectd3, germline or in hematopoietic compartment, including in CD11c+ cells, causes a more severe DSS-induced colitis and increased production of proinflammatory cytokines. Hectd3 mRNA levels were found reduced in colonic tissues of patients with ulcerative colitis (UC), which highlights a potential role for Hectd3 in regulating inflammatory responses in UC. We identified Myd88, a central adaptor in the TLR/IL1R signaling and inflammatory response, as a target for Hectd3 ubiquitination. We demonstrate that Hectd3 directly ubiquitinates Myd88 through K27-linked Poly-Ub chains in a nondegradative manner. Hectd3 KO GM-CSF-bone marrow derived cells treated with the TLR4 ligand lipopolysaccharide (LPS) produced more proinflammatory cytokines, show elevated phosphorylation of NF-κB and IRAK4, as well as elevated association of Myd88 with IRAK4, demonstrating that Hectd3 controls Myd88-IRAK4-NF-κB axis. Inhibition of Myd88 activity rescued colitis severity in the Hectd3 KO mice, including the elevated proinflammatory cytokine production. Thus, our results establish Myd88 as a new target for Hectd3 non-degradative polyubiquitination and restriction of immune colonic inflammation.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038805","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":"Disrupted neuronal expression of autism risk genes and white matter micro-organization after infant Zika infection.","authors":"Venkata-Viswanadh Edara, Sienna Freeman, Maureen Sampson, Kathryn M Moore, Rebecca Richardson, Nils Schoof, Divine Burgess, Michelle J Lee, Gregory K Tharp, Roza Vlasova, Shane Taylor, Ariana Hodjatzadeh, Yihana P Melendez-Alejandro, Samia M Abdallah, Esther W Ndungu, Ava K Mascarenhas, Chao-Hsiung Hsu, Tsang-Wei Tu, Martin Styner, Mehul S Suthar, Mar M Sanchez, Steven E Bosinger, Mark W Burke, Steven A Sloan, Jessica Raper, Ann Chahroudi","doi":"10.1172/jci.insight.203088","DOIUrl":"https://doi.org/10.1172/jci.insight.203088","url":null,"abstract":"<p><p>Congenital and early-life Zika virus (ZIKV) infection can result in neurologic deficits. Precise mechanisms of injury, especially in the more subtle presentation of postnatal infection, are not fully elucidated. Here, we defined the effects of ZIKV on the developing brain using single cell transcriptomics, histopathology and design-based stereology, diffusion MRI, and neurobehavioral assessments in infant rhesus macaques. ZIKV upregulated interferon-stimulated genes in activated microglia and cell death pathways in neurons and downregulated metabolism and differentiation genes in mature oligodendrocytes. Abnormal micro-organization of the corpus collosum and limbic white matter tracts was seen on diffusion weighted imaging. A curated gene set associated with autism spectrum disorder risk was negatively enriched in inhibitory and excitatory neurons from ZIKV-infected infants, with increased emotional reactivity already evident two weeks following infection. From single cells to organism-level behaviors, these results define the pathways and processes disrupted by early-life ZIKV infection.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038752","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}