Loss of the UFM-1 pathway enhances the ER Unfolded Protein Response under stress to improve proteostasis and organismal health in Caenorhabditis elegans

The ubiquitin-like molecule (UBL) Ubiquitin-Fold Modifier 1 (UFM1) has emerged as an important regulator of protein quality control at the endoplasmic reticulum (ER). In humans, dysfunction of the UFM1 pathway is associated with neurodevelopmental diseases and cancer, however the physiological functions of the UFM-1 pathway are not well understood. Here, we used loss-of-function mutants in C. elegans to investigate the role of the UFM-1 pathway in protein homeostasis and organismal health. We found that UFM-1 pathway mutants exhibit enhanced activation of the ER Unfolded Protein Response (UPR ^ER ) in the presence of proteotoxic stress. Loss of the UFM-1 pathway resulted in increased numbers of polyglutamine (polyQ) aggregates in muscle and a change in aggregate composition, consistent with the regulation of protein homeostasis. Interestingly, loss of the ER-anchored components of the UFM-1 pathway also increased polyQ aggregate number, suggesting that the pathway acts at the ER to regulate cytoplasmic protein aggregates. These effects are mediated by the ribosomal subunit RPL-26, a major UFMylation target involved in ribosome-associated quality control. Tissue-specific rescue experiments indicate that the UFM-1 pathway can act cell autonomously and non-cell autonomously from neurons to regulate polyQ aggregates in muscle. Physiologically, UFM-1 pathway mutants exhibit increased survival under proteotoxic stress and increased intestinal barrier integrity in aged animals. Intriguingly, loss of the UFM-1 pathway counteracts the detrimental effects of polyQ expression on lifespan. Our study suggests that under conditions of proteotoxic stress, inhibition of the UFM-1 pathway enhances activation of the UPR ^ER and increases animal healthspan and lifespan.