UBXN1 maintains ER proteostasis and represses UPR activation by modulating translation

Abstract

ER protein homeostasis (proteostasis) is essential for proper folding and maturation of proteins in the secretory pathway. Loss of ER proteostasis can lead to the accumulation of misfolded or aberrant proteins in the ER and triggers the unfolded protein response (UPR). In this study, we find that the p97 adaptor UBXN1 is an important negative regulator of the UPR. Loss of UBXN1 sensitizes cells to ER stress and activates the UPR. This leads to widespread upregulation of the ER stress transcriptional program. Using comparative, quantitative proteomics we show that deletion of UBXN1 results in a significant enrichment of proteins involved in ER-quality control processes including those involved in protein folding and import. Notably, we find that loss of UBXN1 does not perturb p97-dependent ER-associated degradation (ERAD). Our studies indicate that loss of UBXN1 increases translation in both resting and ER-stressed cells. Surprisingly, this process is independent of p97 function. Taken together, our studies have identified a new role for UBXN1 in repressing translation and maintaining ER proteostasis in a p97 independent manner.

Localized K63 ubiquitin signaling is regulated by VCP/p97 during oxidative stress

“…Over 60% of these VCP adaptors were uniquely enriched in the non-cytosolic compartment, suggesting they may be involved in local ubiquitin signaling. Furthermore, FAF2, UBXN1, and NPLOC4, which are among the significantly enriched proteins, have been described in various stress responses within the ER and mitochondria ( 27 , 53 , 54 ). These data indicate that the VCP system may participate in localized ubiquitin signaling following arsenite stress.…”

Papillary Thyroid Cancer Remodels the Genetic Information Processing Pathways

“…Figure 3 shows how the expressions of genes involved in the protein processing in endoplasmic reticulum were regulated in the cancerous part of the thyroid tumor. Interestingly, the ubiquitination gene UBXN1 (UBX domain protein 1), an important negative regulator of the unfolded protein response [102], was significantly up-regulated in the profiled tumor (x (T) = 1.75), but massively down-regulated in both cell lines (x (Φ) = −41.96, x (Θ) = −106.57). While depletion of UBXN1 might be profitable for cancer cell survival and proliferation through protecting against endoplasmic reticulum (ER) stress [103,104], its up-regulation might facilitate migration and invasion of the cancer cells within the thyroid tissue, as reported in prostate cancer [105].…”

Papillary Thyroid Cancer Remodels the Genomic Fabrics of DNA Replication, Repair and Transcription

“…Figure 3 shows how the expressions of genes involved in the protein processing in endoplasmic reticulum were regulated in the cancerous part of the thyroid tumor. Interestingly, the ubiquitination gene UBXN1 (UBX domain protein 1), an important negative regulator of the unfolded protein response [87], was significantly up-regulated in the profiled tumor (xT = 1.75) but massively down-regulated in both cell lines (x (Φ) = -41.96, x (Θ) = -106.57). While depletion of UBXN1 might be profitable for cancer cell survival and proliferation through protecting against endoplasmic reticulum (ER) stress [88,89] its up-regulation might facilitate migration and invasion of the cancer cells within the thyroid tissue as reported in prostate cancer [90].…”