Ube2g2-gp78-mediated HERP polyubiquitination is involved in ER stress recovery

Abstract

A large number of studies have focused on how individual organisms respond to a stress condition, but little attention has been paid to the stress recovery process, such as the endoplasmic reticulum (ER) stress recovery. Homocysteine-induced ER protein (HERP) was originally identified as a chaperone-like protein that is strongly induced upon ER stress. Here we show that, after ER stress induction, HERP is rapidly degraded by Ube2g2-gp78-mediated ubiquitylation and proteasomal degradation. The polyubiquitylation of HERP in vitro depends on a physical interaction between the CUE domain of gp78 and the ubiquitin-like (UBL) domain of HERP, which is essential for HERP degradation in vivo during ER stress recovery. We further show that although HERP promotes cell survival under ER stress, high levels of HERP expression reduce cell viability under oxidative stress conditions, suggesting that HERP plays a dual role in cellular stress adaptation. Together, these results establish the ubiquitin-proteasome-mediated degradation of HERP as a novel mechanism that fine-tunes the stress tolerance capacity of the cell.

HERPUD1 protects against oxidative stress-induced apoptosis through downregulation of the inositol 1,4,5-trisphosphate receptor

“…Interestingly, they also observed that osmotic stress, a known ROS endogenous inductor [49], was also able to induce HERPUD1. In the second work, Yan et al observed that HERPUD1 was induced by reductive agents but not by H 2 O 2 or paraquat [26]. In this case, we attribute the divergent results to the different experimental models and H 2 O 2 concentrations and times studied.…”

“…While HERPUD1 has no enzymatic activity or a defined biological function, this ER protein has shown to regulate ER-associated degradation (ERAD) by interacting with proteins involved in retrotranslocation, ubiquitination and degradation of misfolded proteins [22, 23]. HERPUD1 has cytoprotective roles against ER stress, as it decreases the activity of various caspases, prevents mitochondrial potential collapse and diminishes c-Jun N-terminal kinase (JNK) activation [24–26]. Moreover, our group has recently shown that HERPUD1 acts as a negative regulator of autophagy by inducing the proteasomal degradation of Beclin-1 [27].…”

The CREB3-Herp signalling module limits the cytosolic calcium concentration increase and apoptosis induced by poliovirus

“…CREB3 is a transcription factor associated with ER stress and the ERAD pathway through activation of the Herp gene in particular (Asada et al, 2011;Chan et al, 2011;Liang et al, 2006). Herp plays a key role in ER stress recovery (Yan et al, 2014), and regulates Ca 2+ homeostasis in the ER (Belal et al, 2012;Chan et al, 2004).…”

Plant Virus Infection and the Ubiquitin Proteasome Machinery: Arms Race along the Endoplasmic Reticulum

“…In mammals, there are four ER associated E2 Ub-conjugating enzymes known as UBE2g1, UBE2g2, UBE2j1 and UBE2j2 [20,21]. The Ubc6p has two mammalian homologues named UBE2J1 and UBE2J2 and three plant homologs are named UBC32, 33, and 34 [21].…”

“…Ubc6p and its homologues are ER-integral enzymes, whereas Ubc7p homologs are anchored to the cytoplasmic face of the ER by the integral membrane protein Cue1p [22]. The mammalian UBE2g2 coordinates with gp78 but not HRD1 for ubiquitination of some substrates, suggesting that there are special conditions governing how the E2 and E3 enzymes partner with each other [18,20]. Another conserved component of the retrotranslocon is the p97/cdc48A ATPase that acts on the cytoplasmic face of the ER and helps to pull the ubiquitinated protein from the retrotranslocon toward the proteasome (Figure 1B) [12,23].…”