2. Academic Validation
  3. The BRCC3 regulated by Cdk5 promotes the activation of neuronal NLRP3 inflammasome in Parkinson's disease models

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

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: xyshao@glmc.edu.cn.
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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