Drugs that reprogram the cellular ubiquitin-proteasome system for removal of disease-causing proteins hold great promise as a new type of pharmacology. Small ubiquitin-related modifier (SUMO)-targeted...

The established role of cytosolic and nuclear inclusions of TDP-43 in the pathogenesis of neurodegenerative disorders has multiplied efforts to understand mechanisms that control TDP-43 aggregation and has spurred searches for approaches limiting this process. Formation and clearance of TDP-43 aggregates are controlled by an intricate interplay of cellular proteostasis systems that involve post-translational modifications and frequently rely on spatial control. We demonstrate that attachment of the ubiquitin-like SUMO2 modifier compartmentalizes TDP-43 in promyelocytic leukemia protein (PML) nuclear bodies and limits the aggregation of TDP-43 in response to proteotoxic stress. Exploiting this pathway through proximity-inducing recruitment of TDP-43 to PML triggers a SUMOylation–ubiquitylation cascade protecting TDP-43 from stress-induced insolubility. The protective function of PML is mediated by ubiquitylation in conjunction with the p97 disaggregase. Altogether, we demonstrate that S