4.7 Article

Deubiquitylase OTUD3 Mediates Endoplasmic Reticulum Stress through Regulating Fortilin Stability to Restrain Dopaminergic Neurons Apoptosis

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ANTIOXIDANTS
卷 12, 期 4, 页码 -

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MDPI
DOI: 10.3390/antiox12040809

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OTUD3; ER stress; IRE1 alpha; XBP1s; Fortilin

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OTUD3 knockout mice exhibited loss of nigral dopaminergic neurons and Parkinsonian symptoms, and the underlying mechanism involves the activation of IRE1a-induced ER stress. The ER stress inhibitor TUDCA can alleviate the observed phenotypes. Additionally, OTUD3 regulates the ubiquitination level of Fortilin, affecting the interaction ability of IRE1a with Fortilin and ultimately enhancing the activity of IRE1a.
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 1a (IRE1a)-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-IRE1a/IRE1a, and the expression of X-box binding protein 1-spliced (XBP1s) were remarkably increased after OTUD3 knockdown, which was inhibited by IRE1a 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 IRE1a with Fortilin and finally enhanced the activity of IRE1a. Taken together, we revealed that OTUD3 knockout-induced injury of dopaminergic neurons might be caused by activating IRE1a 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.

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