Sharma, N.; Tanwar, A.; Zheng, C.; Ambudkar, I.; Motiani, R. K.

Transient Receptor Potential Melastatin 2 (TRPM2), a calcium 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 knockout 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 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-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 interferon signaling to pigmentation homeostasis and pigmentary disorders.