RhoGEF Ect2 supports RhoA activity at cell–cell junctions through desmoplakin

TL;DR

This study reveals how desmoplakin helps control RhoA activity at cell junctions, which is important for heart and skin health.

Contribution

The study identifies Ect2 as a new component of cell junctions regulated by desmoplakin.

Findings

Desmoplakin promotes Ect2 localization at desmosomes and cardiac intercalated discs.

Ect2 activity is regulated by PKC in a desmoplakin-dependent manner in cardiac myocytes.

A truncated form of desmoplakin in Carvajal syndrome impairs Ect2 binding and localization.

Abstract

We describe a mechanism by which the desmosome component, desmoplakin, can recruit and control the activity of the contractile signaling regulator RhoA at cardiomyocyte and keratinocyte intercellular junctions, with implications for cardiocutaneous health and disease pathogenesis.

Desmoplakin (DP) is an essential component of the desmosomal adhesion complex, tethering intermediate filaments to sites of intercellular adhesion to confer mechanical integrity to tissues. As a frequent target for mutation in cardiocutaneous syndromes that vary widely in phenotype, DP’s roles as a signaling hub are rapidly emerging. Here, we identify the RhoGEF Ect2 as a previously unappreciated component of intercellular junctions in close association with DP. DP promotes the localization of Ect2 to keratinocyte desmosomes and cardiac intercalated discs, where it maintains active RhoA (Rho-GTP) at the membrane. We demonstrate that Ect2 activity is regulated by PKC in a DP-dependent manner in cardiac myocytes. Finally, a truncated form of DP expressed in patients with Carvajal syndrome associated with severe cardiocutaneous defects is impaired in its ability to bind and localize Ect2 to cell junctions in cardiomyocytes and patient keratinocytes. Our findings delineate an important relationship between a component of the desmosome and a critical regulator of actin cytoskeletal remodeling that could have widespread implications for understanding cardiac and cutaneous health and disease pathogenesis.

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