AMPK Phosphorylates ZDHHC13 to Increase MC1R Activity and Suppress Melanomagenesis

Inherited genetic variations in the melanocortin-1 receptor (MC1R) responsible for human red hair color (RHC) variants are associated with impaired DNA damage repair and increased mela-noma risk. MC1R signaling is critically dependent on palmitoylation, primarily mediated by the protein acyltransferase zinc finger DHHC-type palmitoyltransferase 13 (ZDHHC13). A better understanding of how ZDHHC13 is physiologically activated could help identify approaches to prevent melanomagenesis in redheads. Here, we report that AMP-activated protein kinase (AMPK) phosphorylates ZDHHC13 at S208 to strengthen the interaction between ZDHHC13 and MC1R-RHC, leading to enhanced MC1R palmitoylation in redheads. Consequently, phosphorylation of ZDHHC13 by AMPK increased MC1R-RHC downstream signaling. AMPK activation and MC1R palmitoylation repressed UVB-induced transformation of human melanocytes in vitro and delayed melanomagenesis in vivo in C57BL/6J-MC1R-RHC mice. The importance of AMPK to MC1R signaling was validated in human melanomas where AMPK up-regulation correlated with expression of factors downstream from MC1R signaling and with prolonged patient survival. These findings suggest AMPK activation as a promising strategy to reduce mela-noma risk, especially for individuals with red hair. Significance: Phosphorylation of ZDHHC13 by AMPK at S208 promotes MC1R activation and suppresses melanocyte transfor-mation, indicating activation of AMPK as a potential approach to prevent melanoma in people with red hair.