C-terminal disulfide bond in SUN2 regulate dynamic remodeling of LINC complexesat the nuclear envelope

The LINC complex tethers the cell nucleus to the cytoskeleton to regulate mechanical forces during cell migration, differentiation, and 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 intra- molecular disulfide bond rearrangements. Disruption of the SUN2 terminal disulfide bond compromises SUN2 localization, turnover, LINC complex assembly as well as cytoskeletal organization and cell migration. Moreover, using pharmacological and genetic interventions, 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.