Gene Expression Modulation by the Linker of Nucleoskeleton and Cytoskeleton Complex Contributes to Proteostasis

Cellular mechanisms that act in concert to maintain protein homeostasis (proteostasis) are vital for survival. Nevertheless, subsets of aggregation-prone proteins form toxic aggregates (proteotoxicity) that sometimes underlie the development of neurodegenerative diseases. Proteotoxic aggregates are often deposited in the vicinity of the nucleus, a process that is cytoskeleton-dependent. Accordingly, cytoskeletal dysfunction contributes to pathological hallmarks of various neurodegenerative diseases. Thus, we asked whether the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which bridges these filaments across the nuclear envelope, is needed for the maintenance of proteostasis. Employing model nematodes, we discovered that knocking down LINC components impairs the ability of the worm to cope with proteotoxicity. Knocking down anc-1, which encodes a key component of the LINC complex, modulates the expression of transcription factors and E3 ubiquitin ligases, thereby changing the rates of protein ubiquitination and degradation. Our results establish a link between the LINC complex and aging-associated proteotoxicity.