The BRCC3 regulated by Cdk5 promotes the activation of neuronal NLRP3 inflammasome in Parkinson's disease models

  • Biochem Biophys Res Commun. 2020 Feb 12;522(3):647-654. doi: 10.1016/j.bbrc.2019.11.141.
Xinyu Cheng  1 ,  Shaoye Xu  2 ,  Conghui Zhang  1 ,  Kun Qin  1 ,  Jianguo Yan  3 ,  Xiaoyun Shao  4
Affiliations
  • 1. Department of Human Anatomy, Guilin Medical University, Guilin, 541100, Guangxi, China.
  • 2. Scientific Experiment Center, Guilin Medical University, Guilin, 541100, Guangxi, China.
  • 3. Department of Physiology, Guilin Medical University, Guilin, 541100, Guangxi, China; Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, 541100, Guangxi, China.
  • 4. Department of Human Anatomy, Guilin Medical University, Guilin, 541100, Guangxi, China; Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, 541100, Guangxi, China. Electronic address: [email protected].
PMID: 31787240 DOI: 10.1016/j.bbrc.2019.11.141
Abstract

BRCA1-BRCA2-containing complex subunit 3 (BRCC3), a Lys-63-specific Deubiquitinase, is a member of the JAMM/MPN family of zinc metalloproteases. BRCC3 have been shown to promote the inflammasome activation by deubiquitinating NOD-like Receptor containing pyrin domain 3 (NLRP3). We reported the involvement of neuronal inflammasome in Parkinson's Disease (PD), but the molecular mechanism remains unknown. In this study, we showed that BRCC3 expression was increased in PD models. Knock-down of BRCC3 with shRNA lentivirus decreased NLRP3 neuronal inflammasome. Interestingly, upregulating cyclin-dependent kinase 5 (CDK5) increased the expression of BRCC3 in HEK293 cell, while inhibition of CDK5 decreased the upregulated BRCC3 level in MPP+-induced PD cell model. The interaction between CDK5 and BRCC3 was further confirmed by immunoprecipitation. Moreover, inhibition of CDK5 suppressed the expression of NLRP3, pro-caspase-1, the adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC) and interleukin-1 beta (IL-1β). Besides, inhibition of BRCC3 blocked the increased secretion of IL-1β. Together, these results suggest that Cdk5-mediated BRCC3 expression may play a critical role in neuronal inflammation by regulating the NLRP3 inflammasome in PD.

Keywords
BRCC3; Cdk5; Inflammasome; NLRP3.
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