AMPK Phosphorylates ZDHHC13 to Increase MC1R Activity and Suppress Melanomagenesis.
AMPK Phosphorylates ZDHHC13 to Increase MC1R Activity and Suppress Melanomagenesis.
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DOI：
10.1158/0008-5472.can-22-2595
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发表时间：
2023-04-04
期刊：
影响因子：
11.2
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中科院分区：
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黑皮质素-1受体（MC 1 R）的遗传变异与人类红头发颜色（RHC变体）有关，与受损的DNA损伤修复和增加的黑色素瘤风险有关。MC 1 R信号传导严重依赖于棕榈酰化，主要由蛋白质酰基转移酶ZDHHC 13介导。更好地了解ZDHHC 13是如何在生理上被激活的，可以帮助确定预防红头发黑色素瘤的方法。在这里，我们报告说，AMPK磷酸化ZDHHC 13在S208，以加强ZDHHC 13和MC 1 R-RHC之间的相互作用，导致增强MC 1 R棕榈酰化在红头发。因此，AMPK对ZDHHC 13的磷酸化增加了MC 1 R-RHC下游信号传导。AMPK激活和MC 1 R棕榈酰化抑制UVB诱导的体外人黑素细胞转化，并延迟C57 BL/6 J-MC 1 R-RHC小鼠体内黑素瘤的发生。AMPK对MC 1 R信号传导的重要性在人类黑色素瘤中得到验证，其中AMPK上调与MC 1 R信号传导下游因子的表达和患者生存期延长相关。这些发现表明AMPK激活是一种有希望的降低黑色素瘤风险的策略，特别是对于红发个体。AMPK在S208处对ZDHHC 13的磷酸化促进MC 1 R活化并抑制黑素细胞转化，表明AMPK的活化是预防红发人黑色素瘤的潜在方法。
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 melanoma risk. MC1R signaling is critically dependent on palmitoylation, primarily mediated by the protein acyltransferase ZDHHC13. A better understanding of how ZDHHC13 is physiologically activated could help identify approaches to prevent melanomagenesis in red-heads. Here we report that AMPK phosphorylates ZDHHC13 at S208 to strengthen the interaction between ZDHHC13 and MC1R-RHC, leading to enhanced MC1R palmitoylation in red-heads. 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 upregulation 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 melanoma risk, especially for individuals with red hair. Phosphorylation of ZDHHC13 by AMPK at S208 promotes MC1R activation and suppresses melanocyte transformation, indicating activation of AMPK as a potential approach to prevent melanoma in people with red hair.