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

A large number of studies have focused on how individual organism responses to a stress condition, but little attention was paid to the stress recovery process especially to ER (endoplasmic reticulum) stress recovery. 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 via an Ube2g2-gp78-mediated ubiquitination and proteasomal degradation. The polyubiquitination of HERP in vitro depends on a physical interaction between the CUE domain of gp78 and the 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 reduces 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.