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

Jiang Liu, Ying Wang, Lizhi Song, Linghua Zeng, Weiwei Yi, Ting Liu, Huanzhen Chen, Miao Wang, Zhenyu Ju () and Yu-Sheng Cong ()
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Jiang Liu: Institute of Aging Research, School of Medicine, Hangzhou Normal University
Ying Wang: Institute of Aging Research, School of Medicine, Hangzhou Normal University
Lizhi Song: Institute of Aging Research, School of Medicine, Hangzhou Normal University
Linghua Zeng: Institute of Aging Research, School of Medicine, Hangzhou Normal University
Weiwei Yi: Institute of Aging Research, School of Medicine, Hangzhou Normal University
Ting Liu: Institute of Aging Research, School of Medicine, Hangzhou Normal University
Huanzhen Chen: The First Hospital of Shanxi Medical University
Miao Wang: Institute of Aging Research, School of Medicine, Hangzhou Normal University
Zhenyu Ju: Institute of Aging Research, School of Medicine, Hangzhou Normal University
Yu-Sheng Cong: Institute of Aging Research, School of Medicine, Hangzhou Normal University

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms14186

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