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bioRxiv · 10.64898/2026.03.09.710699

TRPM2 couples cell-autonomous type-I interferon signaling to pigmentation homeostasis

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

Transient Receptor Potential Melastatin 2 (TRPM2), a Ca{superscript 2}-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 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. Key highlights of the studyO_LITRPM2 negatively regulates pigmentation in vitro (mouse and primary human cells) and in vivo (zebrafish and mice). C_LIO_LIUnbiased RNA-sequencing identifies ISG15 as a positive regulator of melanogenesis downstream of TRPM2 silencing. C_LIO_LITRPM2 knockdown generates a cell autonomous type-I-IFN response in melanocytes that induces ISG15 expression. C_LIO_LIISG15 antagonizes global ubiquitination and regulates stability of MITF, the master regulator of pigmentation. C_LI

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Sharma, N., Tanwar, A., Zheng, C., Ambudkar, I., Motiani, R. K.. 2026-03-11. TRPM2 couples cell-autonomous type-I interferon signaling to pigmentation homeostasis. https://doi.org/10.64898/2026.03.09.710699

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