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Parkin increases the risk of colitis by downregulation of VDR via autophagy-lysosome degradation

Zemeng Ma,Junxian Wu,Yuqing Wu,Xiaomeng Sun,Zebing Rao,Naishuang Sun,Yu Fu,Zaikui Zhang,Jingzhou Li,Mengjun Xiao,Q. Zeng,Yuxuan Wu,Chenhua Han,Ding Ding,Hongjie Zhang,Hua Yuan,Jing Zhang,Shuo Yang,Yunzi Chen

Published 2023 in International Journal on Biological Sciences

ABSTRACT

Parkin, an E3 ubiquitin ligase, plays an essential role in mitophagy. Emerging evidence indicates that mitophagy is involved in various processes closely related to immune diseases, including inflammatory bowel diseases (IBD). Here, the authors show that Parkin increases the occurrence of colitis and severe inflammation. Deletion of Parkin resulted in marked reductions in colonic inflammation and exhibited high resistance to DSS-induced colitis. Mechanism investigation indicated that Parkin interacts with Vitamin D receptors (VDR), a critical inhibitory regulator in IBD. Parkin promotes VDR degradation via the p62-related autophagy-lysosome pathway. Comparison of colitis in Parkin-/- and Parkin-/-Vdr-/- mice showed that the protective effect of Parkin deletion against colitis was abolished by VDR deletion. The result suggests that the regulatory effect of Parkin in colitis is a VDR-dependent pathway. Our research provides a new role of Parkin in colitis by downregulating VDR, which provides a potential strategy for treating IBD.

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