Extracellular PKM2 facilitates organ-tissue fibrosis progression

Hongwei Han; Yinwei Zhang; Guangda Peng; Liangwei Li; Jenny Yang; Yi Yuan; Yiting Xu; Zhi-Ren Liu

doi:10.1016/j.isci.2021.103165

Extracellular PKM2 facilitates organ-tissue fibrosis progression

iScience. 2021 Sep 25;24(10):103165. doi: 10.1016/j.isci.2021.103165. eCollection 2021 Oct 22.

Authors

Hongwei Han¹, Yinwei Zhang¹, Guangda Peng¹, Liangwei Li¹, Jenny Yang², Yi Yuan¹, Yiting Xu², Zhi-Ren Liu¹

Affiliations

¹ Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
² Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.

Abstract

Persistent activation of fibroblasts and resistance of myofibroblasts to turnover play important roles in organ-tissue fibrosis development and progression. The mechanism that mediates apoptosis resistance of myofibroblasts is not understood. Here, we report that myofibroblasts express and secrete PKM2. Extracellular PKM2 (EcPKM2) facilitates progression of fibrosis by protecting myofibroblasts from apoptosis. EcPKM2 upregulates arginase-1 expression in myofibroblasts and therefore facilitates proline biosynthesis and subsequent collagen production. EcPKM2 interacts with integrin α_vβ₃ on myofibroblasts to activate FAK-PI3K signaling axis. Activation of FAK-PI3K by EcPKM2 activates downstream NF-κB survival pathway to prevent myofibroblasts from apoptosis. On the other hand, activation of FAK- PI3K by EcPKM2 suppresses PTEN to subsequently upregulate arginase-1 in myofibroblasts. Our studies uncover an important mechanism for organ fibrosis progression. More importantly, an antibody disrupting the interaction between PKM2 and integrin α_vβ₃ is effective in reversing fibrosis, suggesting a possible therapeutic strategy and target for treatment of organ fibrosis.

Keywords: Biological sciences; Cell biology; Molecular biology.