Biology subjects

Juo, P.

Publications and source records attributed to Juo, P..

3 recordsLinked to original sources

bioRxiv2026

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 (UPRER) 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 UPRER and increases animal healthspan and lifespan.

cell biology↗

bioRxiv2020

The p97-UBXN1 complex regulates aggresome formation

The recognition and disposal of misfolded proteins are essential for the maintenance of cellular homeostasis. Perturbations in the pathways that promote degradation of aberrant proteins contribute to a variety of protein aggregation disorders broadly termed proteinopathies. It is presently unclear how diverse disease-relevant aggregates are recognized and processed for degradation. The p97 AAA-ATPase in combination with a host of adaptor proteins functions to identify ubiquitylated proteins and target them for degradation by the ubiquitin-proteasome system or through autophagy. Mutations in p97 cause multi-system proteinopathies; however, the precise defects underlying these disorders are unclear given the large number of pathways that rely on p97 function. Here, we systematically investigate the role of p97 and its adaptors in the process of formation of aggresomes which are membrane-less structures containing ubiquitylated proteins that arise upon proteasome inhibition. We demonstrate that p97 mediates both aggresome formation and clearance in proteasome-inhibited cells. We identify a novel and specific role for the p97 adaptor UBXN1 in the process of aggresome formation. UBXN1 is recruited to ubiquitin-positive aggresomes and UBXN1 knockout cells are unable to form a single aggresome, and instead display dispersed ubiquitin aggregates. Furthermore, loss of p97-UBXN1 results in the increase in Huntingtin polyQ aggregates both in mammalian cells as well as in a C.elegans model of Huntingtons Disease. Together our work identifies evolutionarily conserved roles for p97 and its adaptor UBXN1 in the disposal of protein aggregates.

cell biology↗

bioRxiv2019

The WD40-repeat protein WDR-48 promotes the stability of the deubiquitinating enzyme USP-46 by inhibiting its ubiquitination and degradation

Ubiquitination is a reversible post-translational modification that has emerged as a critical regulator of synapse development and function. However, mechanisms that regulate the deubiquitinating enzymes (DUBs) that are responsible for the removal of ubiquitin from target proteins are poorly understood. We previously showed that the DUB USP-46 removes ubiquitin from the glutamate receptor GLR-1 and regulates it trafficking and degradation in C. elegans. We found that WD40-repeat proteins WDR-20 and WDR-48 bind and stimulate the catalytic activity of USP-46. Here, we identify another mechanism by which WDR-48 regulates USP-46. We found that increased expression of WDR-48, but not WDR-20, promotes USP-46 abundance in mammalian cells in culture and in C. elegans neurons in vivo. Inhibition of the proteasome promotes the abundance of USP-46, and this effect is non-additive with increased expression of WDR-48. We found that USP-46 is ubiquitinated, and expression of WDR-48 reduces the levels of ubiquitin-USP-46 conjugates and increases the half-life of USP-46. A point mutant version of WDR-48 that disrupts binding to USP-46 is unable to promote USP-46 abundance in vivo. Together, these data support a model in which WDR-48 binds and stabilizes USP-46 protein levels by preventing the ubiquitination and degradation of USP-46 in the proteasome. Given that a large number of USPs interact with WDR proteins, we propose that stabilization of DUBs by their interacting WDR proteins may be a conserved and widely used mechanism to control DUB availability and function.

biochemistry↗