Citrullination of pyruvate kinase M2 by PADI1 and PADI3 regulates glycolysis and cancer cell proliferation.

Date publication

mars 2021

Journal

Nature communications

Auteurs

Membres identifiés du Cancéropôle Est :
Dr DAVIDSON Irwin , Dr ROMIER Christophe , Dr NEGRONI Luc , Dr DAUJAT Sylvain

Tous les auteurs :
Coassolo S, Davidson G, Negroni L, Gambi G, Daujat S, Romier C, Davidson I

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/33741961

Résumé

Chromodomain helicase DNA binding protein 4 (CHD4) is an ATPase subunit of the Nucleosome Remodelling and Deacetylation (NuRD) complex that regulates gene expression. CHD4 is essential for growth of multiple patient derived melanoma xenografts and for breast cancer. Here we show that CHD4 regulates expression of PADI1 (Protein Arginine Deiminase 1) and PADI3 in multiple cancer cell types modulating citrullination of arginine residues of the allosterically-regulated glycolytic enzyme pyruvate kinase M2 (PKM2). Citrullination of PKM2 R106 reprogrammes cross-talk between PKM2 ligands lowering its sensitivity to the inhibitors Tryptophan, Alanine and Phenylalanine and promoting activation by Serine. Citrullination thus bypasses normal physiological regulation by low Serine levels to promote excessive glycolysis and reduced cell proliferation. We further show that PADI1 and PADI3 expression is up-regulated by hypoxia where PKM2 citrullination contributes to increased glycolysis. We provide insight as to how conversion of arginines to citrulline impacts key interactions within PKM2 that act in concert to reprogramme its activity as an additional mechanism regulating this important enzyme.

Référence

Nat Commun. 2021 Mar 19;12(1):1718