Integrative Profiling of Lysine Acylome in Sepsis-Induced Liver Injury

Abstract

Sepsis is one of the life-threatening diseases worldwide. Despite the continuous progress in medicine, the specific mechanism of sepsis remains unclear. A key strategy of pathogens is to use post-translational modification to modulate host factors critical for infection. We employed global immunoprecipitation technology for lysine acetylation (Kac), succinylation (Ksu), and malonylation (Kmal) for the first global lysine acylation (Kacy) analysis in a cecum ligation and puncture (CLP) model in mouse. This was performed to reveal the pathogenic mechanism of integrative Kacy and the changes in modification sites. In total, 2230 sites of 1,235 Kac proteins, 1,887 sites of 433 Ksu proteins, and 499 sites of 276 Kmal proteins were quantified and normalized by their protein levels. We focused on 379 sites in 219 upregulated proteins as the integrative Kacy sites of Kac, Ksu, and Kmal on the basis of sirtuins decreased in the CLP group. KEGG pathway analysis of integrative Kacy in 219 upregulated proteins revealed three central metabolic pathways: glycolysis/gluconeogenesis, pyruvate metabolism, and tricarboxylic acid cycle. These findings reveal the key pathogenic mechanism of integrative PTM alteration in terms of the decreased sirtuins level and provide an important foundation for an in-depth study of the biological function of Kacy in sepsis.

Global Profiling of Lysine Acetylation and Lactylation in Kupffer Cells

“…34 Fang et al reported 3731 Kac sites on 1421 cellular proteins in porcine reproductive and respiratory syndrome virus-infected pulmonary alveolar macrophages and hepatocytes, which are the primary cells of the liver; thus, they have become the subject of global acetylome studies over the past decade. 13,35,36 In this study, we identified 2186 Kac sites in 925 ImKC proteins, which were characterized via GO enrichment analysis of Kac proteins. Kac in ImKC is well- enriched in the ribosome, spliceosome, and carbon metabolism categories, as reported in previous studies, by global acetylome DAVID analysis (Figure 3A).…”

“…Large-scale proteomic approaches in mouse liver mitochondria have been performed, 11,12 and studies have been conducted in hepatocytes, HepG2 cells, and AML-12 cells. 13,14 Although various global acetylome studies have been performed on liver and liver-derived cells, no studies involving KCs have been performed.…”