Research Paper Volume 12, Issue 2 pp 1747—1759

K63 ubiquitin chains target NLRP3 inflammasome for autophagic degradation in ox-LDL-stimulated THP-1 macrophages

Zhenfeng Zhou 1, *, , Xiaoyan Zhu 2, *, , Ruihua Yin 1, , Tianwei Liu 3, , Shaonan Yang 1, , Lingyan Zhou 1, , Xudong Pan 1, 3, , Aijun Ma 1, 3, ,

  • 1 Department of Neurology, the Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong, China
  • 2 Department of Intensive Care Unit, the Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong, China
  • 3 Institute of Cerebrovascular Diseases, the Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong, China
* Equal contribution

received: August 23, 2019 ; accepted: January 2, 2020 ; published: January 29, 2020 ;

https://doi.org/10.18632/aging.102710
How to Cite

Copyright © 2020 Zhou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Inflammation, especially involving the NLRP3 inflammasome, is critical to atherosclerotic plaque formation. Enhanced autophagy can inhibit the development of atherosclerosis, and recent studies have revealed that NLRP3 inflammasome can be degraded by autophagy in atherosclerosis. In the present study, we established a foam-cell model to investigate the impact of oxidized low density lipoproteins (ox-LDLs) on autophagy and the inflammasome in atherosclerosis-related inflammation. We observed that ox-LDLs activated NLRP3 inflammasomes in macrophages and restricted autophagy in a time-and dose-dependent manner. We further observed through immunoprecipitation and siRNA knockdown that autophagic degradation of the NLRP3 inflammasome is dependent on K63 polyubiquitation of its NLRP3 subunit and subsequent binding by the adaptor protein p62. Our findings uncover a mechanism by which autophagy inhibits inflammation in atherosclerosis and the role of K63 in that process.

Abbreviations

THP-1 cells: human myeloid leukemia mononuclear cells; Ox-LDLs: oxidized low density lipoproteins; NLRP3: nucleotide-binding domain and leucine-rich repeats containing pyrin domain 3; ASC: the apoptosis-associated speck-like protein containing caspase recruitment domain; AMSH: associated molecule with a Src homology 3 domain of signal transducing adaptor molecule; siRNA: small interfering RNA.