Ubiquitination regulates granulostasis and DRiP accumulation in SGs under heat stress via the E3 ligase MKRN2

Stress granules (SGs) are transient cytoplasmic biomolecular condensates that play a role in the cellular response to proteotoxic stress. It has been previously shown that ubiquitination regulates SG dynamics; however, the specific mechanisms by which ubiquitin affects SGs are not fully understood. Here, using proximity proteomics, we discover that the engagement of several E3 ubiquitin ligases in SGs id dependent on UBA1 activity. A detailed study of the the E3 ubiquitin-protein ligase Makorin 2 (MKRN2) demonstrated that it is localized to SGs in a manner dependent on active ubiquitination. MKRN2 promotes both the proper formation of SGs and their disassembly following stress recovery, by preventing the accumulation of defective ribosomal products (DRiPs) within SGs. Therefore, MKRN2 is a novel regulator of SGs that mediates the maintenance of granulostasis, suggesting that the localization of a subset of E3 ligases into SGs is linked to their capacity to ubiquitinate target proteins.