Nesprin-3: a versatile connector between the nucleus and the cytoskeleton

Abstract

The cytoskeleton is connected to the nuclear interior by LINC (linker of nucleoskeleton and cytoskeleton) complexes located in the nuclear envelope. These complexes consist of SUN proteins and nesprins present in the inner and outer nuclear membrane respectively. Whereas SUN proteins can bind the nuclear lamina, members of the nesprin protein family connect the nucleus to different components of the cytoskeleton. Nesprin-1 and -2 can establish a direct link with actin filaments, whereas nesprin-4 associates indirectly with microtubules through its interaction with kinesin-1. Nesprin-3 is the only family member known that can link the nuclear envelope to intermediate filaments. This indirect interaction is mediated by the binding of nesprin-3 to the cytoskeletal linker protein plectin. Furthermore, nesprin-3 can connect the nucleus to microtubules by its interactions with BPAG1 (bullous pemphigoid antigen 1) and MACF (microtubule-actin cross-linking factor). In contrast with the active roles that nesprin-1, -2 and -4 have in actin- and microtubule-dependent nuclear positioning, the role of nesprin-3 is likely to be more passive. We suggest that it helps to stabilize the anchorage of the nucleus within the cytoplasm and maintain the structural integrity and shape of the nucleus.

Dissecting the cell to nucleus, perinucleus and cytosol

“…This points to the existence of topological borders of the perinuclear region, which we formally call the perinucleus . This is not inconsistent with the previous work of Ketema and Sonnenberg25, who demonstrated that a perinuclear infrastructure includes nesprins and plectins that form, in part, an indirect protein link of the nucleus to the plasma membrane.…”

Networking and anchoring through plectin: a key to IF functionality and mechanotransduction

“…One way how P1 accomplishes its task is by interacting with the ONMspanning protein nesprin-3, which in turn binds to proteins spanning the inner nuclear membrane, establishing a connection between the IF cytoskeleton and the nuclear envelope [54]. This axis might additionally be connected to the actin cytoskeleton via torsinA [55].…”

Nuclear Envelope Disease and Chromatin Organization

“…It was thus not surprising to learn that nesprin-3 connects to the microtubules via the cytoskeletal cross-linkers BPAG1 (bullous pemphigoid antigen 1) (isoform from the dystonin gene; belongs to plakin protein family) and MACF1 (microtubule-actin cross-linking factor 1) [17], nesprin-4 to the molecular motor kinesin 1, and nesprin -1/2 to dynein. It was established long ago that the ER network (a continuation of the ONM) lies alongside the microtubule network [18] and thus one might expect to find that INM/ONM proteins also associate with microtubules.…”

“…However, with the likelihood of further LINC components remaining to be identified and with the number of nesprin family genes/isoforms seeming to be exponentially growing, there is clearly much to learn about the functionality of nucleocytoskeletal connections. Indeed, nesprin-3 appears to play a more passive role than nesprin-1/-2, since it stabilizes nuclear anchorage, rather than orchestrating it [17].…”