{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:41:56Z","timestamp":1785422516095,"version":"3.56.0"},"posted":{"date-parts":[[2025,12,31]]},"group-title":"Cell Biology","reference-count":102,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T00:00:00Z","timestamp":1767139200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/00vqxjy61","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/035yf7a66","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/04cf69335","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/021nxhr62","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Genome-wide association studies (GWAS) have linked dozens of genetic loci to type 1 diabetes (T1D). The\n                  <jats:italic>IFIH1<\/jats:italic>\n                  gene, which encodes the double-stranded RNA sensor MDA5, is one such locus. The E627* single nucleotide polymorphism (SNP) in\n                  <jats:italic>IFIH1<\/jats:italic>\n                  is associated with protection against T1D, while the A946T variant is linked to increased risk. While the E627* variant has been shown to result in a truncated protein and dampen type I interferon (IFN) signaling, its specific role in human pancreatic islet health and function remains unclear. We hypothesized that MDA5\n                  <jats:sup>627<\/jats:sup>\n                  * would protect islet cells from stress-induced dysfunction, identity loss, and cell death. Using CRISPR-Cas9 technology, we introduced the E627* and A946T variants into human pluripotent stem cells (hPSCs) derived from a T1D patient. We differentiated these hPSCs into stem cell-derived islets (SC-islets) and treated them with IFN\u03b1, poly(I:C), and coxsackievirus B3, an enterovirus implicated in T1D pathogenesis. Using single-cell RNA sequencing and an array of functional assays, we investigated the variant impact on both whole SC-islets and their individual cell populations. Our analysis revealed that SC-islets, and their \u03b2, \u03b1, and \u03b4 cell subpopulations, harboring the MDA5\n                  <jats:sup>627<\/jats:sup>\n                  * variant exhibit an attenuated immune response to the various stressors compared to MDA5\n                  <jats:sup>946T<\/jats:sup>\n                  cells. We also report unique, cell-type-specific transcriptional responses that vary across variants. Notably, MDA5\n                  <jats:sup>627<\/jats:sup>\n                  * SC-islets showed reduced apoptosis rates and viral genome expression, as well as attenuated negative effects on mitochondrial function and insulin secretion in response to stress. Overall, our findings demonstrate that a clinically relevant MDA5 variant confers protection by dampening stress-mediated transcriptional responses, reducing cell dysfunction, and preventing apoptosis. These insights provide a mechanistic framework for understanding T1D pathogenesis and offer new avenues for developing preventative therapies.\n                <\/jats:p>","DOI":"10.64898\/2025.12.30.697107","type":"posted-content","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T19:25:11Z","timestamp":1767209111000},"source":"Crossref","is-referenced-by-count":0,"title":["Protective\n                  <i>IFIH1<\/i>\n                  variant reduces immune-mediated islet stress and dysfunction in a type 1 diabetes genetic background"],"prefix":"10.64898","author":[{"given":"Daniel A.","family":"Veronese-Paniagua","sequence":"first","affiliation":[{"name":"Roy and Diana Vagelos Division of Biology and Biomedical Sciences Washington University School of Medicine, St. Louis, MO 63112, USA"},{"name":"Division of Endocrinology, Metabolism, and Lipid Research Washington University School of Medicine, St. Louis, MO 63112, 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