The Nuclear SUMO-Targeted Ubiquitin Quality Control Network Regulates the Dynamics of Cytoplasmic Stress Granules

• Published in: Molecular cell 2020-07, Vol.79 (1), p.54-67.e7
• Main Authors: Keiten-Schmitz, Jan, Wagner, Kristina, Piller, Tanja, Kaulich, Manuel, Alberti, Simon, Müller, Stefan
• Format: Article
• Language: English
• Subjects: ALS; PML; protein quality control; proteotoxic stress; RNF4; SENP; stress granules; StUBL; SUMO; ubiquitin
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2020.05.017

Exposure of cells to heat or oxidative stress causes misfolding of proteins. To avoid toxic protein aggregation, cells have evolved nuclear and cytosolic protein quality control (PQC) systems. In response to proteotoxic stress, cells also limit protein synthesis by triggering transient storage of mRNAs and RNA-binding proteins (RBPs) in cytosolic stress granules (SGs). We demonstrate that the SUMO-targeted ubiquitin ligase (StUbL) pathway, which is part of the nuclear proteostasis network, regulates SG dynamics. We provide evidence that inactivation of SUMO deconjugases under proteotoxic stress initiates SUMO-primed, RNF4-dependent ubiquitylation of RBPs that typically condense into SGs. Impairment of SUMO-primed ubiquitylation drastically delays SG resolution upon stress release. Importantly, the StUbL system regulates compartmentalization of an amyotrophic lateral sclerosis (ALS)-associated FUS mutant in SGs. We propose that the StUbL system functions as surveillance pathway for aggregation-prone RBPs in the nucleus, thereby linking the nuclear and cytosolic axis of proteotoxic stress response. [Display omitted] •RNA-binding proteins are targeted by the SUMO-targeted ubiquitin ligase pathway•SUMO-primed ubiquitylation controls the dynamics of stress granules (SGs)•SUMO-primed ubiquitylation affects SG recruitment of an ALS-associated FUS mutant•SG dynamics are regulated by chain-specific SUMO isopeptidases Keiten-Schmitz et al. reveal a key role of the SUMO-targeted ubiquitin ligase (StUbL) pathway in the cellular stress response. The nuclear StUbL system facilitates resolution of cytosolic stress granules, thereby linking the nuclear and cytosolic axis of the proteotoxic stress response.