The E3 ligase MKRN2 prevents DRiP accumulation in stress granules and maintains granulostasis

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 recruitment of several E3 ubiquitin ligases, VCP cofactors and HSP70 to SGs is dependent on the activity of the E1 ubiquitin ligase UBA1. The RNA-binding E3 ubiquitin-protein ligase Makorin 2 (MKRN2) is strongly depleted from SGs in the absence of UBA1 function. MKRN2 promotes both the proper formation of SGs and their disassembly following stress recovery, by preventing the accumulation of misfolding-prone defective ribosomal products (DRiPs) within SGs. Therefore, MKRN2 is a novel regulator of SGs that mediates the maintenance of granulostasis.