Posttranslational Modification Cross-Talk in Vascular Cells: Molecular Mechanisms and Therapeutic Implications for Atherosclerosis.

Atherosclerosis is driven by coordinated changes in endothelial cells (ECs), macrophages, and vascular smooth muscle cells (VSMCs). Post-translational modifications (PTMs), phosphorylation, acetylation, ubiquitination, SUMOylation, O-GlcNAcylation, palmitoylation, ISGylation, and ADP-ribosylation, integrate metabolic, inflammatory, and mechanical inputs at a limited number of signaling nodes. This review argues that these modifications interact according to four definable relationships rather than merely co-occurring. In competitive cross-talk, two marks contest one acceptor residue, as when O-GlcNAcylation displaces phosphorylation at the Akt site of endothelial nitric oxide synthase. In hierarchical cross-talk, one modification licenses another, as when Ser536 phosphorylation of NF-κB p65 recruits p300 and permits Lys310 acetylation. In enzyme-directed cross-talk, a modification acts on the writer or eraser of a different system, as HDAC9 does on IκB kinases. In cofactor-coupled cross-talk, sirtuin-dependent deacylation and PARP1-dependent ADP-ribosylation draw on one limiting NAD