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

• Published in: Nature communications Vol. 8; no. 1; p. 14186
• Main Authors: Liu, Jiang, Wang, Ying, Song, Lizhi, Zeng, Linghua, Yi, Weiwei, Liu, Ting, Chen, Huanzhen, Wang, Miao, Ju, Zhenyu, Cong, Yu-Sheng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.01.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 38/77; 631/80/82/23; 64/60; 96/106; 96/109; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - physiology; Animals; Apoptosis - physiology; Carrier Proteins - genetics; Carrier Proteins - physiology; Cell Survival - physiology; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress - physiology; Endoribonucleases - metabolism; Gene Knockdown Techniques; HEK293 Cells; Hep G2 Cells; Humanities and Social Sciences; Humans; MCF-7 Cells; Mice; multidisciplinary; Protein Domains - physiology; Protein Stability; Protein-Serine-Threonine Kinases - metabolism; Proteins - metabolism; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Signal Transduction - physiology; Unfolded Protein Response - physiology; X-Box Binding Protein 1 - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14186

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 IRE1α-XBP1 signalling and activates the PERK-eIF2α-CHOP apoptotic pathway by targeting the ER-stress sensor IRE1α. We further demonstrate that DDRGK1 regulates IRE1α protein stability via its interaction with the kinase domain of IRE1α, which is dependent on its ufmylation modification. Altogether, our results provide evidence that DDRGK1 is essential for ER homoeostasis regulation. DDRGK1 is an ER membrane protein that is subject to Ufm1 modification, but its function in ER homeostasis is unknown. Here, the authors show that ufmylated DDRGK1 interacts with and stabilizes the ER-stress sensor protein IRE1a, in turn repressing ER stress and apoptosis.