Palmitoylation-dependent activation of MC1R prevents melanomagenesis

Abstract

The melanocortin-1 receptor (MC1R), a G protein-coupled receptor, plays a crucial role in human and mouse pigmentation1–8. Activation of MC1R in melanocytes by α-melanocyte-stimulating hormone (α-MSH)9 stimulates cAMP signaling and melanin production and enhances DNA repair after UV irradiation (UVR)10–16. Individuals carrying MC1R variants, especially those associated with red hair color, fair skin and poor tanning ability (RHC-variants), are associated with higher risk of melanoma5,17,18,19,20. However, how MC1R activity might be modulated by UV irradiation, why redheads are more prone to developing melanoma, and whether the activity of RHC variants might be restored for therapeutic benefit remain unresolved questions. Here we demonstrate a potential MC1R-targeted intervention strategy to rescue loss-of-function MC1R in MC1R RHC-variants for therapeutic benefit based on activating MC1R protein palmitoylation. Specifically, MC1R palmitoylation, primarily mediated by the protein-acyl transferase (PAT) ZDHHC13, is essential for activating MC1R signaling that triggers increased pigmentation, UVB-induced G1-like cell cycle arrest and control of senescence and melanomagenesis in vitro and in vivo. Using C57BL/6J-MC1Re/eJ mice expressing MC1R RHC-variants we show that pharmacological activation of palmitoylation rescues the defects of MC1R RHC-variants and prevents melanomagenesis. The results highlight a central role for MC1R palmitoylation in pigmentation and protection against melanoma.

Protein palmitoylation and cancer

“…PPT1 is also palmitoylated by ZDHHC3 and ZDHHC7, but in this case, palmitoylation decreases enzyme activity . The function of both PAT (e.g., ZDHHC13, ZDHHC3) and APT (e.g., APT1) enzymes can also be regulated by phosphorylation in cancer and other cells, downstream of different signaling pathways . Thus, a web of interconnected PTMs regulates both ZDHHC and thioesterase localization and activity, with important implications for the regulation of cancer‐associated substrates.…”

“…49,60,61]. Thus, a web of interconnected PTMs regulates both ZDHHC and thioesterase localization and activity, with List of ZDHHC genes, alternative names, associated properties, and links to cancer.…”

“…Cancer links is defined broadly as any literature link between a ZDHHC-family member and a particular cancer, including large-scale and small-scale experimental studies, animal and cell culture studies, and clinical studies, whether functional or correlative. References: ZDHHC2[70,129,130], ZDHHC3[131][132][133], ZDHHC5[87], ZDHHC7[47,134], ZDHHC9[89,92,135,136], ZDHHC11[77,78,137,138], ZDHHC13[49,73], ZDHHC14[82][83][84][85], ZDHHC20[81], ZDHHC23[139]. HPA, Human Protein Atlas (www.proteinatlas.org/).…”

Chemical Synthesis of Native S‐Palmitoylated Membrane Proteins through Removable‐Backbone‐Modification‐Assisted Ser/Thr Ligation

“…[6] Dysfunction of S-palmitoylation can cause neurological diseases, immune diseases,o rc ancers.F or example,d epalmitoylation of melanocortin-1 receptor (MC1R) stimulates melanogenesis. [7] S-palmitoylation on programmed death ligand-1 (PD-L1) promotes tumor growth. [8] Structure-function relationships of S-palmitoylated membrane proteins need to be studied to decipher the role of S-palmitoylation and facilitate drug discovery.…”

Chemical Synthesis of Native S‐Palmitoylated Membrane Proteins through Removable‐Backbone‐Modification‐Assisted Ser/Thr Ligation

“…Dysfunction of S‐palmitoylation can cause neurological diseases, immune diseases, or cancers. For example, depalmitoylation of melanocortin‐1 receptor (MC1R) stimulates melanogenesis . S‐palmitoylation on programmed death ligand‐1 (PD‐L1) promotes tumor growth .…”