Dynamic regulation of LINC complex composition and function across tissues and contexts

Abstract

The concept of mechanotransduction to the nucleus through a direct force transmission mechanism has fascinated cell biologists for decades. Central to such a mechanism is the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which spans the nuclear envelope to couple the cytoplasmic cytoskeleton to the nuclear lamina. In reality, there is not one LINC complex identity, but instead a family of protein configurations of varied composition that exert both shared and unique functions. Regulated expression of LINC complex components, splice variants, and mechanoresponsive protein turnover mechanisms together shape the complement of LINC complex forms present in a given cell type. Disrupting specific gene(s) encoding LINC complex components therefore gives rise to a range of organismal defects. Moreover, evidence suggests that the mechanical environment remodels LINC complexes, providing a feedback mechanism by which cellular context influences the integration of the nucleus into the cytoskeleton. In particular, evidence for crosstalk between the nuclear and cytoplasmic intermediate filament networks communicated through the LINC complex represents an emerging theme in this active area of ongoing investigation.

The transmembrane protein Syndecan regulates stem cell nuclear properties and cell maintenance

“…We reasoned that Sdc depletion could impair a relay from the plasma membrane to the nucleus, which would in turn alter nuclear properties. The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex is a conserved multiprotein complex that connects the cytoskeleton with the nucleoskeleton, allowing transmission of mechanical force from the cell surface to the nucleus, regulating nuclear deformation, positioning and functions (Horn, 2014; King, 2023). The Drosophila LINC complex consists of two KASH proteins, Klarsicht (Klar) and Msp300, and two SUN proteins, Klaroid (Koi) and the testes-specific SPAG4 (Figure 3B) (Horn, 2014).…”

“…Knockdown of Klar or Koi produced only modest nuclear elongation (Figure 3D) and nuclear lobing was unaffected (Figure 3E). This suggests Sdc function is unlikely to be fully accounted for by individual LINC complex proteins, although these proteins may act redundantly (Horn, 2014; King, 2023).…”

Altered nuclear envelope homeostasis is a key pathogenic event in C9ORF72-linked ALS/FTD

“…Here, we investigated the role of mechanical stress on the nucleus as a significant driver of NPC and NE injury. Mechanical forces generated by the cytoskeleton can be transmitted onto the nucleus via the linker of nucleoskeleton and cytoskeleton (LINC) complex [29][30][31] . This is a multiprotein complex embedded in the NE and is the main structure that links the nucleus to the plasma membrane.…”

Life at the crossroads: the nuclear LINC complex and vascular mechanotransduction

“…In contrast to the extensive literature on endothelial cell signaling in general, how the nucleus participates in mechanotransduction is poorly understood. The LINC (Linker of Nucleoskeleton and Cytoskeleton) complex resides in the nuclear envelope and bridges the nucleus and cytoskeleton, and it has recently been implicated in mechanotransduction processes ( Janota et al, 2020 ; King, 2023 ). Although most of the published work is in non-vascular cells, some recent studies examine LINC complex functions in the vasculature ( Mannion and Holmgren, 2023 ).…”