{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:59:03Z","timestamp":1791392343380,"version":"4.3.3"},"reference-count":54,"publisher":"National Academy of Sciences","issue":"41","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"HHS | NIH | NIAID | Division of Intramural Research","doi-asserted-by":"publisher","award":["ZIA AI001185"],"award-info":[{"award-number":["ZIA AI001185"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["ZIA AR041205"],"award-info":[{"award-number":["ZIA AR041205"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,10,13]]},"abstract":"<jats:p>\n                    MATRIN3 (MATR3) is a broadly expressed nuclear RNA-binding protein. However, the mechanisms by which MATR3 maintains human cellular health remain poorly understood. In this study, we employed gene editing to model MATR3 deficiency in human induced pluripotent stem cells (iPSCs) and the HAP1 haploid cell line. To investigate the consequences of MATR3 loss-of-function, we profiled gene expression changes by RNA sequencing, which revealed significant upregulation of interferon-stimulated genes (ISGs) in MATR3-deficient cells, indicating activation of innate immune signaling. To elucidate the mechanism underlying ISG upregulation, we identified direct targets of MATR3 using photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP). In one of these targets,\n                    <jats:italic toggle=\"yes\">TDRD3<\/jats:italic>\n                    , a gene required for R-loop metabolism in conjunction with Topoisomerase III Beta (\n                    <jats:italic toggle=\"yes\">TOP3B<\/jats:italic>\n                    ),\n                    <jats:italic toggle=\"yes\">MATR3<\/jats:italic>\n                    loss induced the incorporation of a 53-nucleotide-long poison exon that triggered nonsense-mediated decay and subsequent reduction in its expression. Consistent with dysfunction of the TDRD3\u2013TOP3B complex, MATR3 loss led to the aberrant accumulation of cytoplasmic RNA\u2013DNA hybrids, which activated the inflammatory cGAS\u2013STING pathway. These findings uncover a previously unrecognized role of MATR3 in maintaining RNA processing fidelity and cellular homeostasis, and establish a mechanistic link between MATR3 dysfunction and innate immune activation. This molecular cascade has significant implications, hinting at a plausible disease mechanism underlying MATR3-associated neurodegenerative diseases, and other conditions of MATR3 deficiency yet to be discovered. Furthermore, these molecular insights provide potential avenues for diagnosing and treating MATR3 loss-of-function in humans.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2608835123","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:35:51Z","timestamp":1791390951000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["<i>MATRIN3<\/i>\n                    deficiency in human cells triggers an autoinflammatory response via cGAS\u2013STING activation"],"prefix":"10.1073","volume":"123","author":[{"given":"Zohirul","family":"Islam","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}],"name":"Integrative Immunobiology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, 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Islam MATRIN3 deficiency leads to cGAS-STING activation. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE216830. 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