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

Abstract

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 associated 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-1α2, 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.

Nesprin proteins: bridging nuclear envelope dynamics to muscular dysfunction

“…Disruption of the LINC complex poses a significant hurdle to cell polarization, with fibroblasts harboring defects in nuclear lamin A/C struggling with nuclear polarization and migration [ 26 ]. Engineered mice with genetic mutations in the LINC complex or lamin manifest aberrant synaptic nuclear positioning in skeletal muscle neuromuscular junctions [ 15 , 27 ]. These findings address a fundamental inquiry: How do nuclear membrane proteins influence cellular structure and functionality?…”

“…They accentuate the significance of the microtubule network, Nesprin proteins, and other cytoskeletal components in maintaining nuclear shape and preventing damage. Forming a sophisticated molecular network beneath the nuclear envelope, the LINC complex, connected with nuclear membrane protein emerin and the nuclear lamina, facilitates mechanical force transfer and direct regulation from the cytoskeleton to the nuclear genome, highlighting its crucial role in transmitting mechanical signals [ 15 , 38 , 39 ]. Mutations in LINC complex components have been implicated in various nuclear envelope diseases in muscle physiology, including DCM and EDMD, among other striated muscle disorders.…”

“…2 B). The integrity of the LINC complex is vital for maintaining nuclear structure and function, underscoring its significance in cell development and function [ 15 , 25 , 27 , 35 , 40 , 41 ]. Understanding the LINC complex and its components not only elucidates muscle disease mechanisms but also unveils potential treatments for nuclear envelope disorders and related diseases.…”

“…Nesprin-1 and Nesprin-2, classified as ‘giant’ isoforms, stand out as some of the largest proteins known, boasting impressive molecular weights of 1.01 MDa and 796 kDa, respectively. Spanning 146 and 116 exons, respectively, these proteins share a remarkable 64% structural homology, emphasizing their close relationship and functional parallels [ 15 , 42 , 43 ]. Originally identified as markers for vascular smooth muscle cell differentiation and synaptic muscle components, subsequent research has unveiled their extensive expression across diverse cell types, underscoring their profound biological significance [ 15 , 42 , 44 – 46 ].…”

“…Particularly, Nesprin proteins, integral components of the LINC complex, emerge as pivotal mediators in this intricate interplay, influencing cellular morphology, structure, and mechanical stability [ 14 ]. Understanding their role is paramount, especially in mechanically sensitive tissues like cardiac and striated muscles, where disruptions in the LINC complex are implicated in various muscular disorders [ 15 , 16 ]. This review delves into the multifaceted functions of Nesprin proteins within the LINC complex, elucidating their involvement in muscular diseases such as DCM and EDMD, and exploring novel therapeutic strategies aimed at rectifying Nesprin-related pathologies.…”