DHHC12 serves as a critical nutrient-responsive switch that couples amino acid sensing to insulin secretion

Protein palmitoylation covalently attaches the energy metabolite palmitate to target proteins, yet how it is regulated by nutrient status remains elusive. Here, we identify the palmitoyltransferase DHHC12 as a critical nutrient-responsive switch, coupling amino acid availability to insulin secretion. Amino acid deficiency activates the kinase GCN2, which phosphorylates COPA at Thr777, enabling its function as an adaptor for the CRL4 E3 ligase complex and leading to ubiquitination of DHHC12 on two critical cysteine residues (Cys127 and Cys133, with Cys127 within the catalytic DHHC motif) and its subsequent degradation. In male mice, loss of Dhhc12 impairs insulin secretion and causes glucose intolerance. DHHC12 palmitoylates SYT7 to promote glucose-stimulated insulin exocytosis. The physiological relevance of this pathway is underscored by two human DHHC12 variants: the hypoglycemia-associated L196P mutant evades degradation, whereas the hyperglycemia-linked N238I mutant is constitutively degraded. Together, our findings establish the GCN2-COPA-DHHC12 axis as a direct nutrient-sensing mechanism that couples amino acid availability to systemic glucose homeostasis. Men et al. show that amino acid deprivation activates GCN2 to phosphorylate COPA, recruiting CRL4 E3 ligase that ubiquitinates DHHC12 at its catalytic cysteine for degradation. This blocks SYT7 palmitoylation and insulin secretion. Human DHHC12 variants with opposing stability correlate with fasting glucose, validating clinical importance.