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.

Keywords: DCM and EDMD; mechanotransduction; microtubule; nesprin; nuclear envelope LINC complex; nuclear positioning.

Figure 1.. Protein domains of nesprin-1G and nesprin-1α2.

(A) Giant nesprin-1 structure consists of three major domains: (i) tandem actin binding CH domains (yellow) (ii) central rod of SRs (blue) (iii) NE-targeting KASH domain, consisting of a transmembrane (TM) domain and luminal KASH peptide (red). Additionally, a highly conserved-terminal adaptive domain (AD) at C-terminus serves to structurally stabilises the spectrin repeat (SR)s. (B) Nesprin-1α2 is a small muscle specific isoform, equivalent to the C-terminal region of nesprin-1G containing the last six spectrin repeats and the KASH domain. Nesprin-1 interacting protein binding domains and validated DCM/EDMD pathological mutations are indicated within this highly conserved C-terminal region.

Figure 2.. Roles of the nesprins and the LINC complex at the nuclear envelope.

(A) Nesprin isoforms localise at the ONM interact with SUN1/2 to form the LINC complex, physically linking the cytoskeleton to the nucleus. The LINC complex associates with the chromatin through interactions with the nuclear lamina and chromatin binding partners such as emerin and BAF. At the ONM nuclear membrane, giant nesprin isoforms-1 and -2 can directly bridge the nucleus to the actin cytoskeleton, whereas nesprin-3 associates with the muscle-specific intermediate filament protein desmin via plectin, and short nesprin isoform nesprin-1α2 associates with MTs via KLC-1/2 and AKAP6. The scaffolding protein AKAP6 can in turn anchor centrosomal proteins, PCM1, PCNT, AKAP9 to the NE, and form a cAMP-PKA signalling hub, which may have a role in NE calcium handling via interacting with RyRs at the sarcoplasmic reticulum. Smaller nesprin isoforms can also be found at the INM where they interact with lamin A/C and emerin. (B) Nesprin mutations (red stars) may cause LINC complex disruption and uncoupling of the cytoskeleton from the nucleus, resulting in structural defects such as abnormal nucleus shape, size, migration or positioning, or pathophysiological activation of signalling pathways or mechanosensitive transcription factors, which ultimately leading to cellular dysfunction and cardiac and skeletal muscle myopathies.

Figure 3.. Microtubules in nuclear positioning and organisation in striated muscle cells.

(A) Cardiomyocyte differentiation results in mono- or bi-nucleated cells, where the nuclei are centrally positioned, and cells are extensively interconnected by IDs. Conversely, during myogenesis myoblasts fuse into a multi-nucleated myofibers, where nuclei are peripherally anchored amongst sarcomeres. (B) In both skeletal and cardiac muscle cells, MT nucleation can occur from the nucleus as centrosomal proteins are recruited by nesprin-1α2 via AKAP6 to the NE facilitating the formation of the perinuclear MT cage. (C) During myogenesis, the association of nesprin-1α2 with MTs, via the MT motor kinesin-1, mediates the dynamic movement of nuclei by either transforming the nucleus into a kinesin-1 cargo on MT tracks, or by exerting repelling forces through cross-linked MTs of neighbouring nuclei until equidistant.