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

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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 | Puceat, Michel | Morales Rodriguez, Blanca | Goldmann, Wolfgang, H | Dal Ferro, Matteo | Biferi, Maria-Grazia | Knaus, Petra | Worman, Howard, J | Muchir, Antoine | Bonne, Gisele

Edité par CCSD ; Oxford University Press (OUP) -

International audience. 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.

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