Deubiquitylase OTUD3 Mediates Endoplasmic Reticulum Stress through Regulating Fortilin Stability to Restrain Dopaminergic Neurons Apoptosis
Ling Chen,
Xuejie Huan,
Fengju Jia,
Zhen Zhang,
Mingxia Bi,
Lin Fu,
Xixun Du,
Xi Chen,
Chunling Yan,
Qian Jiao,
Hong Jiang
Affiliations
Ling Chen
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
Xuejie Huan
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
Fengju Jia
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
Zhen Zhang
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
Mingxia Bi
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
Lin Fu
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
Xixun Du
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
Xi Chen
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
Chunling Yan
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
Qian Jiao
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
Hong Jiang
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
OTU domain-containing protein 3 (OTUD3) knockout mice exhibited loss of nigral dopaminergic neurons and Parkinsonian symptoms. However, the underlying mechanisms are largely unknown. In this study, we observed that the inositol-requiring enzyme 1α (IRE1α)-induced endoplasmic reticulum (ER) stress was involved in this process. We found that the ER thickness and the expression of protein disulphide isomerase (PDI) were increased, and the apoptosis level was elevated in the dopaminergic neurons of OTUD3 knockout mice. These phenomena were ameliorated by ER stress inhibitor tauroursodeoxycholic acid (TUDCA) treatment. The ratio of p-IRE1α/IRE1α, and the expression of X-box binding protein 1-spliced (XBP1s) were remarkably increased after OTUD3 knockdown, which was inhibited by IRE1α inhibitor STF-083010 treatment. Moreover, OTUD3 regulated the ubiquitination level of Fortilin through binding with the OTU domain. OTUD3 knockdown resulted in a decrease in the interaction ability of IRE1α with Fortilin and finally enhanced the activity of IRE1α. Taken together, we revealed that OTUD3 knockout-induced injury of dopaminergic neurons might be caused by activating IRE1α signaling in ER stress. These findings demonstrated that OTUD3 played a critical role in dopaminergic neuron neurodegeneration, which provided new evidence for the multiple and tissue-dependent functions of OTUD3.
