Nuclear Matrix Archives - The NOMIS Foundation

The LINC complex tethers the cell nucleus to the cytoskeleton to regulate mechanical forces during cell migration, differentiation, and various diseases. The function of LINC complexes relies on the interaction between highly conserved SUN and KASH proteins that form higher-order assemblies capable of load bearing. These structural details have emerged from in vitro assembled LINC complexes; however, the principles of in vivo assembly remain obscure. Here, we report a conformation-specific SUN2 antibody as a tool to visualize LINC complex dynamics in situ. Using imaging, biochemical, and cellular methods, we find that conserved cysteines in SUN2 undergo KASH-dependent inter- and intramolecular disulfide bond rearrangements. Disruption of the SUN2 terminal disulfide bond compromises SUN2 localization, turnover, LINC complex assembly in addition to cytoskeletal organization and cell migration. Moreover, using pharmacological and genetic perturbations, we identify components of the ER lumen as SUN2 cysteines redox state regulators. Overall, we provide evidence for SUN2 disulfide bond rearrangement as a physiologically relevant structural modification that regulates LINC complex functions. © 2023 Sharma and Hetzer.

Repeated rounds of nuclear envelope (NE) rupture and repair have been observed in laminopathy and cancer cells and result in intermittent loss of nucleus compartmentalization. Currently, the causes of NE rupture are unclear. Here, we show that NE rupture in cancer cells relies on the assembly of contractile actin bundles that interact with the nucleus via the linker of nucleoskeleton and cytoskeleton (LINC) complex. We found that the loss of actin bundles or the LINC complex did not rescue nuclear lamina defects, a previously identified determinant of nuclear membrane stability, but did decrease the number and size of chromatin hernias. Finally, NE rupture inhibition could be rescued in cells treated with actin-depolymerizing drugs by mechanically constraining nucleus height. These data suggest a model of NE rupture where weak membrane areas, caused by defects in lamina organization, rupture because of an increase in intranuclear pressure from actin-based nucleus confinement.

Publications in Nuclear Matrix by NOMIS researchers

Disulfide bond in SUN2 regulates dynamic remodeling of LINC complexes at the nuclear envelope

Nuclear envelope rupture is induced by actin-based nucleus confinement