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<p>Post-translational modifications (PTMs) of pyruvate kinase M2 (PKM2) play a vital role in regulating its activity and function. Recently, we found PKM2 can undergo crotonylation in vascular smooth muscle cell (VSMC) phenotypic switching. However, the role of PKM2 crotonylation remains unknown. Here, we verify a crucial role of PKM2 crotonylation in VSMC metabolic reprogramming. In PDGF-BB-induced synthetic VSMCs, PKM2 crotonylation was upregulated and promotes its nuclear translocation, thereby facilitating the expression of <i>Glut1</i> and <i>Ldha</i>. Furthermore, crotonylation facilitated the dimeric formation of PKM2. Then we identified the highly conserved crotonylation site at K305 across different species. The crotonylation of PKM2 was compromised by PKM2 K305 mutation, resulting in the suppression of PKM2 dimeric configuration and nuclear relocation, and ultimately reducing glycolysis rate. Furthermore, PKM2 K305 crotonylation was necessary for VSMC phenotypic switching in vitro and intimal hyperplasia in vivo via infection of PKM2 recombinant adenovirus. In summary, PKM2 K305 crotonylation facilitates VSMC aerobic glycolysis by enhancing PKM2 dimeric form.</p><p></p>

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PKM2 crotonylation reprograms glycolysis in VSMCs, contributing to phenotypic switching

  • 期刊论文

  • 发表日期：

    2025年4月3日

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  • Shan-Hu Cao,
  • Ru-Yuan Ma,
  • Tong Cao,
  • Tao Hu,
  • Shu Yang,
  • Zhi-Yan Ren,
  • Jiang-Ling Niu,
  • Ming-Qi Zheng,
  • Mei Han,
  • Li-Hua Dong

摘要

Post-translational modifications (PTMs) of pyruvate kinase M2 (PKM2) play a vital role in regulating its activity and function. Recently, we found PKM2 can undergo crotonylation in vascular smooth muscle cell (VSMC) phenotypic switching. However, the role of PKM2 crotonylation remains unknown. Here, we verify a crucial role of PKM2 crotonylation in VSMC metabolic reprogramming. In PDGF-BB-induced synthetic VSMCs, PKM2 crotonylation was upregulated and promotes its nuclear translocation, thereby facilitating the expression of Glut1 and Ldha. Furthermore, crotonylation facilitated the dimeric formation of PKM2. Then we identified the highly conserved crotonylation site at K305 across different species. The crotonylation of PKM2 was compromised by PKM2 K305 mutation, resulting in the suppression of PKM2 dimeric configuration and nuclear relocation, and ultimately reducing glycolysis rate. Furthermore, PKM2 K305 crotonylation was necessary for VSMC phenotypic switching in vitro and intimal hyperplasia in vivo via infection of PKM2 recombinant adenovirus. In summary, PKM2 K305 crotonylation facilitates VSMC aerobic glycolysis by enhancing PKM2 dimeric form.