The Molecular Mechanism Of DDRGK1 In Endoplasmic Reticulum Homeostasis Maintenance By Regulating IRE1?

The endoplasmic reticulum(ER)homeostasis is essential for cell function and survival,and its imbalance induces the ER stress and activates the unfolded protein response(UPR).In mammalian cells,there are three branches of the UPR signaling pathway known as PERK-eIF2?,IRE1?-XBP1,and ATF6.These three pathways work together to maintain homeostasis in the ER and promote cell survival.However,during prolonged or overwhelming ER stress,the UPR fails to restore ER homoeostasis,and induces apoptosis.DDRGK1 is located in the ER and its PCI domain helps to recruit UFL1,C53 and UFSP2 to form a large protein complex,which is involved in Ufmylation system.Ufmylation is one of the newly-identified ubiquitination-like modifications,and only two substrates have been identified.As a substrate of Ufmylation,DDRGK1 is also required for Ufmylation on other substrates.However,the biological functions of DDRGK1 are largely unknown.In this study,we found that depletion of DDRGK1 significantly inhibits the IRE1?-XBP1 signaling pathway and induces apoptosis.We further demonstrate the interaction and co-localization of DDRGK1 with IRE1?,and DDRGK1 regulates the stability of IRE1? protein levels.Taken together,our results suggest that DDRGK1 is involved in the maintenance of ER homeostasis by regulating IRE1?-XBP1 signaling pathway.