Cofilin-1 phosphorylation catalyzed by ERK1/2 alters cardiac actin dynamics in dilated cardiomyopathy caused by lamin A/C gene mutation

• Published in: Human molecular genetics Vol. 27; no. 17; pp. 3060 - 3078
• Main Authors: Chatzifrangkeskou, Maria, Yadin, David, Marais, Thibaut, Chardonnet, Solenne, Cohen-Tannoudji, Mathilde, Mougenot, Nathalie, Schmitt, Alain, Crasto, Silvia, Di Pasquale, Elisa, Macquart, Coline, Tanguy, Yannick, Jebeniani, Imen, Pucéat, Michel, Morales Rodriguez, Blanca, Goldmann, Wolfgang H, Dal Ferro, Matteo, Biferi, Maria-Grazia, Knaus, Petra, Bonne, Gisèle, Worman, Howard J, Muchir, Antoine
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.09.2018; Oxford University Press (OUP)
• Subjects: Actins - genetics; Actins - metabolism; Adolescent; Adult; Animals; Cardiology and cardiovascular system; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - metabolism; Cardiomyopathy, Dilated - pathology; Case-Control Studies; Cofilin 1 - genetics; Cofilin 1 - metabolism; Female; Genetics; Heart - physiology; Human health and pathology; Humans; Lamin Type A - genetics; Lamin Type A - metabolism; Life Sciences; Male; Mice; Middle Aged; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Mutation; Original; Phosphorylation; Signal Transduction; Young Adult
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddy215

Abstract Hyper-activation of extracellular signal-regulated kinase (ERK) 1/2 contributes to heart dysfunction in cardiomyopathy caused by mutations in the lamin A/C gene (LMNA cardiomyopathy). The mechanism of how this affects cardiac function is unknown. We show that active phosphorylated ERK1/2 directly binds to and catalyzes the phosphorylation of the actin depolymerizing factor cofilin-1 on Thr25. Cofilin-1 becomes active and disassembles actin filaments in a large array of cellular and animal models of LMNA cardiomyopathy. In vivo expression of cofilin-1, phosphorylated on Thr25 by endogenous ERK1/2 signaling, leads to alterations in left ventricular function and cardiac actin. These results demonstrate a novel role for cofilin-1 on actin dynamics in cardiac muscle and provide a rationale on how increased ERK1/2 signaling leads to LMNA cardiomyopathy.