{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:08:22Z","timestamp":1785434902016,"version":"3.56.0"},"posted":{"date-parts":[[2026,3,11]]},"group-title":"Cell Biology","reference-count":77,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["IA\/I\/19\/2\/504651"],"award-info":[{"award-number":["IA\/I\/19\/2\/504651"]}],"id":[{"id":"https:\/\/ror.org\/04reqzt68","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017220","name":"Regional Centre for Biotechnology","doi-asserted-by":"crossref","award":["R25226"],"award-info":[{"award-number":["R25226"]}],"id":[{"id":"10.13039\/100017220","id-type":"DOI","asserted-by":"crossref"}]},{"award":["Z01-DE00438-38"],"award-info":[{"award-number":["Z01-DE00438-38"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Transient Receptor Potential Melastatin 2 (TRPM2), a Ca\u00b2\u207a-permeable cation channel, regulates innate and adaptive immunity and has recently been implicated in vitiligo, an autoimmune pigmentary disorder. However, whether TRPM2 exerts cell-autonomous immunoregulatory functions and how such signaling intersects with pigmentation remain unknown. Here, we reveal an unexpected role for TRPM2 as an intrinsic suppressor of pigmentation through type-I interferon (IFN) signaling in melanocytes. Pharmacological inhibition, genetic silencing, and gain-of-function approaches demonstrate that TRPM2 negatively regulates melanogenesis\n                  <jats:italic>in vitro<\/jats:italic>\n                  . Notably, TRPM2-deficient zebrafish and TRPM2\u207b\/\u207b mice exhibit enhanced pigmentation\n                  <jats:italic>in vivo<\/jats:italic>\n                  , establishing physiological relevance. Transcriptomic profiling uncovers autonomous activation of the type-I-IFN pathway upon TRPM2 loss, leading to induction of interferon-stimulated gene 15 (ISG15). Mechanistically, ISG15 attenuates global ubiquitination and stabilizes microphthalmia-associated transcription factor (MITF), the master regulator of melanogenesis, thereby promoting pigmentation. Collectively, our findings define a previously unrecognized TRPM2\u2013type-I-IFN\u2013ISG15\u2013MITF signaling axis that functionally integrates cell-autonomous immune surveillance pathways with pigmentary control. Further, it provides a conceptual framework linking type-I interferon signaling to pigmentation homeostasis and pigmentary disorders.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Key highlights of the study<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>\n                        TRPM2 negatively regulates pigmentation\n                        <jats:italic>in vitro<\/jats:italic>\n                        (mouse and primary human cells) and\n                        <jats:italic>in vivo<\/jats:italic>\n                        (zebrafish and mice).\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Unbiased RNA-sequencing identifies ISG15 as a positive regulator of melanogenesis downstream of TRPM2 silencing.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>TRPM2 knockdown generates a cell autonomous type-I-IFN response in melanocytes that induces ISG15 expression.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>ISG15 antagonizes global ubiquitination and regulates stability of MITF, the master regulator of pigmentation.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.09.710699","type":"posted-content","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T03:15:15Z","timestamp":1773285315000},"source":"Crossref","is-referenced-by-count":0,"title":["TRPM2 couples cell-autonomous type-I interferon signaling to pigmentation homeostasis"],"prefix":"10.64898","author":[{"given":"Nutan","family":"Sharma","sequence":"first","affiliation":[{"name":"Laboratory of Calciomics and Systemic Pathophysiology (LCSP), Regional Centre 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