A critical role of DDRGK1 in endoplasmic reticulum homoeostasis via regulation of IRE1α stability

Disturbance of endoplasmic reticulum (ER) homoeostasis induces ER stress and leads to activation of the unfolded protein response (UPR), which is an adaptive reaction that promotes cell survival or triggers apoptosis, when homoeostasis is not restored. DDRGK1 is an ER membrane protein and a critical component of the ubiquitin-fold modifier 1 (Ufm1) system. However, the functions and mechanisms of DDRGK1 in ER homoeostasis are largely unknown. Here, we show that depletion of DDRGK1 induces ER stress and enhances ER stress-induced apoptosis in both cancer cells and hematopoietic stem cells (HSCs). Depletion of DDRGK1 represses IRE1 alpha-XBP1 signalling and activates the PERK-eIF2 alpha-CHOP apoptotic pathway by targeting the ER-stress sensor IRE1 alpha. We further demonstrate that DDRGK1 regulates IRE1 alpha protein stability via its interaction with the kinase domain of IRE1 alpha, which is dependent on its ufmylation modification. Altogether, our results provide evidence that DDRGK1 is essential for ER homoeostasis regulation.