A Glance at the Nuclear Envelope Spectrin Repeat Protein 3

Abstract

Nuclear envelope spectrin repeat protein 3 (nesprin-3) is an evolutionarily-conserved structural protein, widely-expressed in vertebrate cells. Along with other nesprin family members, nesprin-3 acts as an essential component of the linker of nucleoskeleton and cytoskeleton (LINC) complex. Naturally, nesprin-3 shares many functions with LINC, including the localization of various cellular structures and bridging of the nucleoskeleton and cytoskeleton, observed in vitro. When nesprin-3 was knocked down in vivo, using zebrafish and mouse models, however, the animals were minimally affected. This paradoxical observation should not limit the physiological importance of nesprin-3, as recently, nesprin-3 has reignited the interest of the research community in studies on cancer cells migration. Moreover, nesprin-3 also plays an active role in certain developmental conditions such as adipogenesis and spermatogenesis, although more studies are needed. Meanwhile, the various protein binding partners of nesprin-3 should also be emphasized, as they are necessary for maintaining the structure of nesprin-3 and enabling it to carry out its various physiological and pathological functions. Nesprin-3 promises to further our understanding of these complex cellular events. Therefore, this review will focus on nesprin-3, examining it from a genetic, structural, and functional perspective. The final part of the review will in turn address the limitations of existing research and the future perspectives for the study of nesprin-3.

Nuclear mechanosignaling in striated muscle diseases

“…Nesprins provide many of the linkages between the outer nuclear membrane and cytoskeletal proteins. Nesprins generally are composed of three domains: a highly conserved C-terminus which interacts with the SUN (Sad1p, UNC-84) protein at the outer nuclear membrane (ONM), a spectrin repeat domain, and a diverse N-terminus that binds to cytoskeleton structures (Stroud, 2018;Liao et al, 2019). Nesprin-1/2 can also directly bind to actin filaments (Chancellor et al, 2010;Zhou et al, 2018), while nesprin-1α2 indirectly interacts with microtubule structures through Kinesin 1 FIGURE 1 Schematic of the intracellular environment of a mature cardiomyocyte, illustrating mechanical coupling between the ECM the costamere, the sarcomere, the nucleoskeleton, and chromatin.…”

“…Nesprin-1/2 can also directly bind to actin filaments ( Chancellor et al, 2010 ; Zhou et al, 2018 ), while nesprin-1α2 indirectly interacts with microtubule structures through Kinesin 1 ( Mislow et al, 2002 ; Briand and Collas, 2020 ). Nesprin-3 indirectly binds to intermediate filaments through plectin ( Wilhelmsen et al, 2005 ), and microtubules through Microtubule-Actin Cross-linking Factor (MACF) and Bullous pemphigoid antigen 1 (BPAG1) ( Ketema and Sonnenberg, 2011 ; Liao et al, 2019 ). The interaction between Nesprin and SUN forms the basic structure of LINC that can propagate forces between the cytoskeleton and the nucleus.…”

Nuclear Mechanotransduction in Skeletal Muscle

“…Nesprin1-α2 is required for the correct positioning of myonuclei [77,120,132,133] and MT nucleation from the NE [119], by recruiting A-Kinase Anchoring Protein-450 to the NE [77]. Nesprin-3 lacks actin-binding domains but can indirectly connect to the cytoskeleton by binding to another protein with tandem actin-binding calponin homology domain [134]. Although nesprin-3 exists as two isoforms, nesprin-3α and nesprin-3β, only nesprin-3α can attach to the cytoskeleton.…”

Nuclear Dynamics and Chromatin Structure: Implications for Pancreatic Cancer

“…Other proteins reside primarily in the ONM, including nesprins, key transmembrane ONM proteins involved in nuclear mechanosensing [22]. The cytoplasmic N-terminal region of nesprins 1-4 contains spectrin repeats and other nesprin isoform-specific domains, allowing individual nesprins to interact with actin filaments, microtubules, and/or intermediate filaments [22][23][24][25]. The C-termini of nesprins possess KASH (Klarsicht, ANC-1, or Syne Homology) domains that interact with the C-termini of SUN proteins within the nuclear envelope lumen (Figure 1).…”