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
- 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
Received: August 23, 2019 Accepted: January 2, 2020 Published: January 29, 2020
https://doi.org/10.18632/aging.102710How to Cite
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.