ACSS2-mediated MYH9 crotonylation drives Zika virus-induced vascular smooth muscle cell phenotypic switching

Abstract

Zika virus (ZIKV) infection represents an emerging cause of cardiovascular pathology, yet the molecular mechanisms driving virus-induced vascular injury remain incompletely defined. This investigation identifies a crotonylation pathway underlying ZIKV-induced vascular disease. We demonstrate that ZIKV infection upregulates the metabolic regulator ACSS2, consequently elevating intracellular crotonyl-CoA levels. This metabolic shift drives lysine crotonylation of the cytoskeletal protein MYH9 at the critical K82 residue, triggering a pathological transition of vascular smooth muscle cells from contractile to synthetic phenotypes. This cellular reprogramming promotes aortic injury across multiple animal models, including northern pig-tailed macaques and A129 mice. Genetic ablation of ACSS2 substantially attenuated both the phenotypic switching and disease progression. Furthermore, we developed a targeted therapeutic peptide that effectively inhibits MYH9-K82 crotonylation and mitigates pathological vascular remodeling. These findings not only elucidate ACSS2-mediated protein crotonylation as a fundamental mechanism in ZIKV-induced vasculopathy but also present a promising precision therapeutic strategy for treating virus-induced proliferative vascular diseases.

Keywords: ACSS2; CP: Microbiology; Kcr; MYH9; Zika virus; phenotypic switching.