LINC Complexes and Their Role in Human Disease

Abstract

Abstract In most metazoan cell types, the nucleus occupies a clearly defined region of the cytoplasm. For instance in epithelial cells, it is commonly positioned close to the basal membrane, whereas in skeletal muscle fibres, the majority of nuclei are uniformly distributed adjacent to the plasma membrane. A few muscle cell nuclei, however, cluster beneath the postsynaptic membrane. In certain cell types, the nucleus may be repositioned according to cell cycle phase or cell activity. Each of these situations requires that nuclei be physically coupled to the cytoskeleton. This is accomplished in large part by LINC (linker of the nucleoskeleton and cytoskeleton) complexes. These structures consist of inner nuclear membrane SUN (Sad1p‐UNC‐84)‐domain proteins that function as transluminal tethers for outer nuclear membrane KASH ‐domain proteins. Together, SUN–KASH pairs function as links in a molecular chain that couples cytoskeletal elements, including motor proteins, to nuclear components. In addition to having obligate roles in nuclear positioning and chromatin organisation, LINC complexes may also function in mechanotransduction. The fact that a number of human diseases have been associated with LINC complex defects indicates that in many cell types these represent essential structures at the interface between the nucleus and cytoplasm. Key Concepts The nuclear envelope forms the interface between the nucleus and cytoplasm. Its most prominent features are the inner and outer nuclear membranes (INM and ONM) separated by a narrow (∼50 nm) gap, the perinuclear space (PNS). SUN domain proteins of the INM function as transluminal tethers for KASH domain proteins in the ONM. The nucleoplasmic domain of SUN proteins provides binding sites for both chromatin proteins and components of the nuclear lamina. KASH domain proteins represent attachment sites at the nuclear envelope for a variety of cytoskeletal elements, including motor proteins. SUN–KASH pairs, which span both nuclear membranes, are known as LINC (linker of the nucleoskeleton and cytoskeleton) complexes and mechanically couple nuclear structures to the cytoskeleton. LINC complexes have essential roles in nuclear migration and positioning in multiple cell types. During meiosis, LINC complexes have an essential role in telomere‐led chromosome movement, a process that facilitates homologous chromosome pairing and synapsis. LINC complexes are thought to mediate the transmission of mechanical signals to the nucleus: mechanotransduction.