AMPK Phosphorylates ZDHHC13 to Increase MC1R Activity and Suppress Melanomagenesis

Abstract

Inherited genetic variations in the melanocortin-1 receptor MC1R palmitoylation repressed UVB-induced transformation of (MC1R) responsible for human red hair color (RHC) variants are human melanocytes in vitro and delayed melanomagenesis in vivo in associated with impaired DNA damage repair and increased melaC57BL/6J-MC1R-RHC mice. The importance of AMPK to MC1R noma risk. MC1R signaling is critically dependent on palmitoylation, signaling was validated in human melanomas where AMPK up-primarily mediated by the protein acyltransferase zinc finger DHHC-regulation correlated with expression of factors downstream from type palmitoyltransferase 13 (ZDHHC13). A better understanding MC1R signaling and with prolonged patient survival. These findings of how ZDHHC13 is physiologically activated could help identify suggest AMPK activation as a promising strategy to reduce melaapproaches to prevent melanomagenesis in redheads. Here, we noma risk, especially for individuals with red hair. report that AMP-activated protein kinase (AMPK) phosphorylates ZDHHC13 at S208 to strengthen the interaction between ZDHHC13 Significance: Phosphorylation of ZDHHC13 by AMPK at S208 and MC1R-RHC, leading to enhanced MC1R palmitoylation in promotes MC1R activation and suppresses melanocyte transforredheads. Consequently, phosphorylation of ZDHHC13 by AMPK mation, indicating activation of AMPK as a potential approach to increased MC1R-RHC downstream signaling. AMPK activation and prevent melanoma in people with red hair.