Linker of nucleoskeleton and cytoskeleton complex proteins in cardiac structure, function, and disease

Abstract

The linker of nucleoskeleton and cytoskeleton (LINC) complex, composed of proteins within the inner and the outer nuclear membranes, connects the nuclear lamina to the cytoskeleton. The importance of this complex has been highlighted by the discovery of mutations in genes encoding LINC complex proteins, which cause skeletal or cardiac myopathies. Herein, this review summarizes structure, function, and interactions of major components of the LINC complex, highlights how mutations in these proteins may lead to cardiac disease, and outlines future challenges in the field.

Keywords: cardiomyopathies; cell nucleus; myocytes, cardiac.

Figure 1. The LINC complex in the cardiomyocyte

The LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1 and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1α and 2α may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and 2 may localize to the INM. Various proteins are associated with the LINC complex, such as Emerin and Luma, and are thought to play an important role in cardiac function. Chromatin directly interacts with Lamin A/C and indirectly with Emerin and Lamin B Receptor (LBR) via Barrier to Auto-integration Factor (BAF) and Heterochromatin Protein 1 (HP1), respectively. NPC, Nuclear Pore Complex; M, M-band.