Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045-2507.
Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, CO 80045-2507.
Proc Natl Acad Sci U S A. 2022 Feb 15;119(7). doi: 10.1073/pnas.2119678119.
-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 ill-defined. We demonstrate that the cytoplasmic scaffolding protein, gravin-α/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-α and demyristoylates these sites. In brown and white adipocytes, lysine myristoylation of gravin-α is required for signaling via β- and β-adrenergic receptors (β-ARs), which are G protein-coupled receptors (GPCRs). Lysine myristoylation of gravin-α drives β-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.
甘氨酸的豆蔻酰化是一种不可逆的修饰，长期以来一直被认为控制着蛋白质的定位和功能。相比之下，赖氨酸豆蔻酰化的生物学作用仍未得到明确界定。我们证明，细胞质支架蛋白gravin-α/A 激酶锚定蛋白 12 在其羧基末端蛋白激酶 A（PKA）结合域内的两个赖氨酸残基上发生豆蔻酰化。组蛋白去乙酰化酶 11（HDAC11）与 gravin-α 的相邻区域结合，并脱去这些位点的豆蔻酰基。在棕色和白色脂肪细胞中，gravin-α 的赖氨酸豆蔻酰化对于通过β-和β-肾上腺素能受体（β-AR）的信号转导是必需的，β-AR 是 G 蛋白偶联受体（GPCR）。gravin-α 的赖氨酸豆蔻酰化将 β-AR 驱动到脂筏膜微区，导致 PKA 激活和下游信号转导，最终导致保护性生热基因表达。这些发现将可逆的赖氨酸豆蔻酰化定义为控制 GPCR 信号转导的一种机制，并强调了抑制 HDAC11 以用于治疗目的来操纵脂肪细胞表型的潜力。
