Authors
Nutan Sharma, Abhishek Tanwar, Changyu Zheng, Indu Ambudkar, Rajender K Motiani
Published in
The Journal of biological chemistry. Pages 113624. Oct 08, 2026. Epub Oct 08, 2026.
Abstract
Transient Receptor Potential Melastatin 2 (TRPM2), a Ca2+-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 in vitro. Notably, TRPM2-deficient zebrafish and TRPM2-/- mice exhibit enhanced pigmentation in vivo, establishing physiological relevance. Transcriptomic profiling uncovers autonomous activation of the type-I-IFN pathway upon TRPM2 loss, leading to induction of IFN-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-type-I-IFN-ISG15-MITF signaling axis that functionally integrates cell-autonomous immune surveillance pathways with pigmentary control. Further, it provides a conceptual framework linking type-I-IFN signaling to pigmentation homeostasis and pigmentary disorders.
PMID:
42849734
Bibliographic data and abstract were imported from PubMed on 09 Oct 2026.
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