Lactylation of PKM2 Suppresses Inflammatory Metabolic Adaptation in Pro-inflammatory Macrophages

Abstract

Emerging evidence suggests that metabolic adaptation is a vital hallmark and prerequisite for macrophage phenotype transition. Pyruvate kinase M2 (PKM2) is an essential molecular determinant of metabolic adaptions in pro-inflammatory macrophages. Post-translational modifications play a central role in the regulation of PKM2. However, doubt remains on whether lactylation in PKM2 exists and how lactylation modulates the function of PKM2. For the first time, our study reports that lactate inhibits the Warburg effect by activating PKM2, promoting the transition of pro-inflammatory macrophages towards a reparative phenotype. We identify PKM2 as a lactylation substrate and confirm that lactylation occurs mainly at the K62 site. We find that lactate increases the lactylation level of PKM2, which inhibits its tetramer-to-dimer transition, promoting its pyruvate kinase activity and reducing nuclear distribution. In short, our study reports a novel post-translational modification type in PKM2 and clarifies its potential role in regulating inflammatory metabolic adaptation in pro-inflammatory macrophages.

Lactylation-Related Gene Signature Effectively Predicts Prognosis and Treatment Responsiveness in Hepatocellular Carcinoma

“…Wang et al investigated the lactylation of PKM2 and confirmed that PKM2 lactylation could suppress inflammatory metabolic adaptation in proinflammatory macrophages. This finding confirmed the result of our analysis, which indicated that the modification site K62 on PKM2 was in the structural domain and may affect the function of the protein [16].…”

“…However, HCC may develop resistance toward these chemicals and targeted drugs, which can attenuate treatment efficacy [2,3]; in addition, the high heterogeneity of HCC has become an obstacle in HCC treatment [4]. Therefore, Pharmaceuticals 2023, 16, 644 2 of 19 developing an effective prognostic model that is useful in selecting proper treatment approaches and drugs for HCC treatment is an urgent issue.…”

The emerging era of lactate: A rising star in cellular signaling and its regulatory mechanisms

“…Blocking such vicious feedback mitigates microglial dysfunction and cognitive deficits in AD mouse model 8 . A direct lactylation of PKM2 at lysine 62 (K62) that creates a negative feedback to glycolysis is also proposed 134 . This inhibitory regulation of glycolysis by lactate promotes the transition of proinflammatory macrophages to a reparative phenotype via suppressing their metabolic adaptation 134 .…”

“…8 A direct lactylation of PKM2 at lysine 62 (K62) that creates a negative feedback to glycolysis is also proposed. 134 This inhibitory regulation of glycolysis by lactate promotes the transition of proinflammatory macrophages to a reparative phenotype via suppressing their metabolic adaptation. 134 Such phenotypic transition of macrophages allows tissue to recover from the inflammatory response.…”

“…134 This inhibitory regulation of glycolysis by lactate promotes the transition of proinflammatory macrophages to a reparative phenotype via suppressing their metabolic adaptation. 134 Such phenotypic transition of macrophages allows tissue to recover from the inflammatory response. Other studies however suggest lactate-driven histone lactylation favors reparative gene activation in macrophages.…”