DHHC protein-dependent palmitoylation protects regulator of G-protein signaling 4 from proteasome degradation

Regulator of G-protein signaling 4 (RGS4), an intracellular modulator of G-protein coupled receptor (GPCR)-mediated signaling, is regulated by multiple processes including palmitoylation and proteasome degradation. We found that co-expression of DHHC acyltransferases (DHHC3 or DHHC7), but not their acyltransferase-inactive mutants, increased expression levels of RGS4 but not its Cys2 to Ser mutant (RGS4C2S). DHHC3 interacts with and palmitoylates RGS4 but not RGS4C2S in vivo. Palmitoylation prolongs the half-life of RGS4 by over 8-fold and palmitoylated RGS4 blocked α_1A-adrenergic receptor-stimulated intracellular Ca²⁺ mobilization. Together, our findings revealed that DHHC proteins could regulate GPCR-mediated signaling by increasing RGS4 stability. Structured summary: MINT- 8049215: Rgs4 (uniprotkb: P49799) physically interacts (MI: 0915) with DHHC3 (uniprotkb: Q8R173) by anti-tag coimmunoprecipitation (MI: 0007).