COMMD3 mediates melanin synthesis through both clusterin-PAX3 axis and copper-dependent tyrosinase activity in skin pigmentation

BACKGROUND: Pigmentation-related disorders mainly revolve around abnormal melanogenesis, but the regulatory mechanisms remain unclear. Recent reports have found that COMMD3 plays a role in promoting melanin synthesis. OBJECTIVES: This study aims to investigate the molecular mechanisms and relation with copper homeostasis of a novel pigment-promoting gene, COMMD3, in skin pigmentation. METHODS: A UV-induced pigmentation murine model was created by UVB irradiation for examining the function of COMMD3 in acquired hyperpigmentation. Intracellular copper content was measured to determine the effect of COMMD3 on tyrosinase activity. After suppressing COMMD3 by gene knockdown (KD) in the B16F10 cell line and the UVB-induced pigmented murine model, RNA sequencing was conducted to identify potential signaling pathways underlying COMMD3 regulating melanogenesis. RESULTS: COMMD3 modulating melanogenesis was observed in UV-induced pigmented murine models and B16F10s. RNA sequencing and validation supported that suppressing COMMD3 leads to an increase in clusterin (CLU), decreasing PAX3 and its nuclear translocation, ultimately resulting in a reduction of melanogenesis. Concurrently, as a copper transporter, a decrease in COMMD3 expression caused intracellular copper accumulation, which lowered tyrosinase activity and reduced melanin production. After using the copper chelator ammonium tetrathiomolybdate to alleviate copper accumulation caused by COMMD3 deficiency, repress CLU expression, and restore PAX3, leading to increasing melanin content in melanogenesis. CONCLUSION: Our findings demonstrate that COMMD3 plays an important role in regulating melanogenesis. COMMD3 regulates melanogenesis via CLU-PAX3 axis and adjusts tyrosinase activity through intracellular copper levels. The insights provide a mechanistic rationale and potential therapeutic strategy for mitigating acquired skin pigmentation disorders.