Spatial protein quality control requires a functional GET pathway to prevent proteotoxicity

The proper management of misfolded proteins is an essential biological process that is required for the survival of all organisms. Previous work has demonstrated that misfolded proteins can be spatially sequestered into membrane-less compartments to facilitate their degradation. Soluble cytoplasmic misfolded proteins are sequestered in the juxtanuclear quality control compartment (JUNQ), and insoluble cytoplasmic misfolded proteins are sequestered into the insoluble protein deposit (IPOD). It is still unknown if there are upstream targeting pathways necessary for regulating JUNQ and IPOD formation. Here we investigated the role of ER targeting on JUNQ and IPOD formation. We find that the GET pathway is necessary for JUNQ formation. Inefficiencies in the GET pathway contribute to premature IPOD formation, and a defective GET pathway inhibits JUNQ formation altogether. Notably, we find the GET pathway's role in JUNQ formation is required for cell survival and loss of GET pathway function is only toxic under proteotoxic stress. Overall, we identify a new role for the GET pathway in regulating spatial PQC and demonstrate that spatial quality control is essential for cell health and survival.