Reversible lysine fatty acylation of an anchoring protein mediates adipocyte adrenergic signaling

N-myristoylation on glycine is an irreversible modification that has long been recognized to govern protein localization and function. In contrast, the biological roles of lysine myristoylation remain illdefined. We demonstrate that the cytoplasmic scaffolding protein, gravin-alpha/A kinase-anchoring protein 12, is myristoylated on two lysine residues embedded in its carboxyl-terminal protein kinase A (PKA) binding domain. Histone deacetylase 11 (HDAC11) docks to an adjacent region of gravin-alpha and demyristoylates these sites. In brown and white adipocytes, lysine myristoylation of gravin-alpha is required for signaling via beta(2)- and beta(3)-adrenergic receptors (beta-ARs), which are G protein-coupled receptors (GPCRs). Lysine myristoylation of gravin-alpha drives beta-ARs to lipid raft membrane microdomains, which results in PKA activation and downstream signaling that culminates in protective thermogenic gene expression. These findings define reversible lysine myristoylation as a mechanism for controlling GPCR signaling and highlight the potential of inhibiting HDAC11 to manipulate adipocyte phenotypes for therapeutic purposes.

Automated summary

This article highlights the importance of lysine myristoylation in regulating protein localization and function, as well as its role in controlling G protein-coupled receptor signaling. Inhibiting HDAC11 may have therapeutic potential for manipulating adipocyte phenotypes.