Nesprin-1: novel regulator of striated muscle nuclear positioning and mechanotransduction

Nesprins (nuclear envelope spectrin repeat proteins) are multi-isomeric scaffolding proteins. Giant nesprin-1 and-2 localise to the outer nuclear membrane, interact with SUN (Sad1p/ UNC-84) domain-containing proteins at the inner nuclear membrane to form the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex, which, in association with lamin A/C and emerin, mechanically couples the nucleus to the cytoskeleton. Despite ubiquitous expression of nesprin giant isoforms, pathogenic mutations in nesprin-1 and-2 are asso-ciated with tissue-specific disorders, particularly related to striated muscle such as dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy. Recent evidence suggests this muscle-specificity might be attributable in part, to the small muscle specific isoform, nesprin-1 alpha 2, which has a novel role in striated muscle function. Our current understanding of muscle-specific functions of nesprin-1 and its isoforms will be summarised in this review to provide insight into potential pathological mechanisms of nesprin-related muscle disease and may inform potential targets of therapeutic modulation.

Automated summary

Nesprins are multi-isomeric scaffolding proteins that play important roles in linking the nucleus to the cytoskeleton. Pathogenic mutations in nesprin-1 and-2 are associated with tissue-specific disorders, including dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy. Recent evidence suggests that a small muscle-specific isoform of nesprin-1, called nesprin-1 alpha 2, may contribute to the muscle-specificity of these diseases. This review summarizes our current understanding of the muscle-specific functions of nesprin-1 and its isoforms, with the goal of providing insights into the potential pathological mechanisms and therapeutic targets of nesprin-related muscle diseases.