The Dual Roles of Lamin A/C in Mechanosensation to Compressive Force

Abstract

Abstract Cellular mechanosensation is a complex physiological process coupling alterations in the external environment and cellular behaviors. Over the past decade, the role of the nucleus in mechanosensation has gained increasing attention. Our research found that lamin A/C, a component of the nuclear envelope, plays a dual role in the mechanosensation of macrophages in response to compressive force. Our findings indicated that hydrostatic compressive force downregulated lamin A/C protein via the cytoskeleton. Consequently, this lamin A/C deficiency enhanced compressive-force-induced inflammatory cytokines secretion and proliferative impairment. Unexpectedly, lamin A deficiency also inhibits compressive force-induced DNA damage and interferon regulatory factor 4 (IRF4) up-regulation. Our findings suggest that lamin A/C is involved in multiple mechanosensation mechanisms. Mechanistically, lamin A/C deficiency augments nuclear permeability, facilitates the activation of yes-associated protein 1 (YAP1) and promotes force-induced nuclear translocation of YAP1. These mechanisms have been validated to favor mechanosensation. Conversely, we also found that lamin A/C deficiency led to detachment of components of linker of nucleoskeleton and cytoskeleton (LINC) complex, which impeded intracellular mechanotransmission. In summary, lamin A/C can promote some responses of macrophages to mechanical compression but inhibits others. It is involved in two distinct mechanisms: enhancing nuclear permeability to transcription factors and impairing mechanotransmission by disrupting the LINC complex's connection to the nucleus.