Nesprins and Lamins in Health and Diseases of Cardiac and Skeletal Muscles

Abstract

Since the discovery of the inner nuclear transmembrane protein emerin in the early 1990s, nuclear envelope (NE) components and related involvement in nuclei integrity and functionality have been highly investigated. The NE is composed of two distinct lipid bilayers described as the inner (INM) and outer (ONM) nuclear membrane. NE proteins can be specifically “integrated” in the INM (such as emerin and SUN proteins) or in the ONM such as nesprins. Additionally, flanked to the INM, the nuclear lamina, a proteinaceous meshwork mainly composed of lamins A and C completes NE composition. This network of proteins physically interplays to guarantee NE integrity and most importantly, shape the bridge between cytoplasmic cytoskeletons networks (such as microtubules and actin) and the genome, through the anchorage to the heterochromatin. The essential network driving the connection of nucleoskeleton with cytoskeleton takes place in the perinuclear space (the space between ONM and INM) with the contribution of the LINC complex (for Linker of Nucleoskeleton to Cytoskeleton), hosting KASH and SUN proteins interactions. This close interplay between compartments has been related to diverse functions from nuclear integrity, activity and positioning through mechanotransduction pathways. At the same time, mutations in NE components genes coding for proteins such as lamins or nesprins, had been associated with a wide range of congenital diseases including cardiac and muscular diseases. Although most of these NE associated proteins are ubiquitously expressed, a large number of tissue-specific disorders have been associated with diverse pathogenic mutations. Thus, diagnosis and molecular explanation of this group of diseases, commonly called “nuclear envelopathies,” is currently challenging. This review aims, first, to give a better understanding of diverse functions of the LINC complex components, from the point of view of lamins and nesprins. Second, to summarize human congenital diseases with a special focus on muscle and heart abnormalities, caused by mutations in genes coding for these two types of NE associated proteins.

Emery‐Dreifuss muscular dystrophy type 4: A new SYNE1 mutation associated with hypertrophic cardiomyopathy masked by a perinatal distress‐related spastic diplegia

“…The mutation reported is localized into a central domain composed of multiple spectrin repeats (SR), which supports interactions with other proteins such as emerin, with the Emerin Binding Domain (EBD), or lamins, with the Lamin Binding Domain (LBD) . This network of proteins physically interplays to guarantee nuclear envelop integrity and shapes the bridge between cytoplasmic cytoskeletons networks and the genome …”

Microtubule Organization in Striated Muscle Cells

“…Anchoring of MTOC proteins depends on a muscle-specific isoform of the outer nuclear membrane protein nesprin-1, nesprin-1α [60,178], which belongs to the Klarsicht, ANC-1, and Syne homology (KASH) protein family [179,180]. KASH proteins form, together with Sad1 and UNC-84 (SUN) proteins at the inner nuclear membrane, the linker of nucleoskeleton and cytoskeleton (LINC) complex [181][182][183]. Depletion of nesprin-1α dispersed PCM1, PCNT, and AKAP9 from the nuclear envelope and premature expression of nesprin-1α in undifferentiated (i.e., myogenin-negative) myoblasts was sufficient to recruit a fraction of endogenous PCM1 as well as an ectopically expressed centrosome-targeting domain of PCNT and AKAP9 (i.e., PACT domain) [60].…”

“…The importance of nuclear envelope proteins that connect the nucleus to the microtubule cytoskeleton for nuclear positioning has been underlined by a multitude of studies using a variety of cell types or model organisms [219,226] (Figure 3). The LINC complex has emerged as a key player in microtubule-based nuclear positioning [181,183]. In mammalian skeletal muscle, the KASH protein nesprin-1 has been first discovered to be critical for nuclear clustering at the NMJ, where its expression is higher compared to non-synaptic nuclei in mature muscle [227,228].…”

Hippo Signaling-Mediated Mechanotransduction in Cell Movement and Cancer Metastasis

“…Nesprin-1 and−2 are expressed ubiquitously in human. Both proteins encode an actin binding domain (ABD) at the N-terminus, a rod domain with several spectrin repeats that provide an interaction hub for Emerin and Lamin, and a C-terminal KASH domain inserted into the outer nuclear membrane (Janin and Gache, 2018). Nesprin-1 has recently been reported as playing a role in promoting nuclear localization of YAP in response to mechanical stretching to induce nuclear deformation in cultured cells (Driscoll et al, 2015).…”