PKM2 promotes pulmonary fibrosis by stabilizing TGF-β1 receptor I and enhancing TGF-β1 signaling


Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease, and its molecular mechanism is still poorly understood.On September 21, 2022, Zhou Honggang, Yang Cheng, Yang Guang and Ning Wen of Nankai University published a joint communication on Science Advances, entitled "PKM2 promotes purple fiber by stabilizing TGF- β 1 receptor I and enhancing TGF- β 1 signaling, which shows that pyruvate kinase M2 (PKM2) directly interacts with Smad7 and enhances transforming growth factor- β 1 (TGF- β 1) Signal transduction to promote the progression of fibrosis. Total PKM2 expression and tetramer form were elevated in lungs and fibroblasts (derived from mice with bleomycin (BLM) induced pulmonary fibrosis). Pkm2 deletion significantly reduced BLM induced fibrosis progression, myofibroblast differentiation, and TGF- β 1 Signal conduction is activated.
       Further research shows that PKM2 tetramer enhances TGF by directly binding with Smad7 on its MH2 domain- β 1 Signal conduction, thus interfering with Smad7 and TGF- β Type I receptor (T β R1) to reduce T β R1 ubiquitination and stabilization of T β R1。 The pharmacological enhancement of PKM2 tetramer by TEPP-46 can promote BLM induced pulmonary fibrosis, while the destruction of tetramer by compound 3k can alleviate the progress of fibrosis. In conclusion, this study shows how PKM2 regulates TGF- β Signal transduction is a key factor in the progression of fibrosis.