PMID- 36936774 OWN - NLM STAT- MEDLINE DCOM- 20230327 LR - 20230327 IS - 2235-2988 (Electronic) IS - 2235-2988 (Linking) VI - 13 DP - 2023 TI - BPOZ-2 is a negative regulator of the NLPR3 inflammasome contributing to SARS-CoV-2-induced hyperinflammation. PG - 1134511 LID - 10.3389/fcimb.2023.1134511 [doi] LID - 1134511 AB - INTRODUCTION: Inflammation play important roles in the initiation and progression of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), septic shock, clotting dysfunction, or even death associated with SARS-CoV-2 infection. However, the pathogenic mechanisms underlying SARS-CoV-2-induced hyperinflammation are still largely unknown. METHODS: The animal model of septic shock and ALI was established after LPS intraperitoneal injection or intratracheal instillation. Bone marrow-derived macrophages (BMDMs) from WT and BPOZ-2 KO mouse strains were harvested from the femurs and tibias of mice. Immunohistology staining, ELISA assay, coimmunoprecipitation, and immunoblot analysis were used to detect the histopathological changes of lung tissues and the expression of inflammatory factors and protein interaction. RESULTS AND CONCLUSIONS: We show a distinct mechanism by which the SARS-CoV-2 N (SARS-2-N) protein targets Bood POZ-containing gene type 2 (BPOZ-2), a scaffold protein for the E3 ubiquitin ligase Cullin 3 that we identified as a negative regulator of inflammatory responses, to promote NLRP3 inflammasome activation. We first demonstrated that BPOZ-2 knockout (BPOZ-2 KO) mice were more susceptible to lipopolysaccharide (LPS)-induced septic shock and ALI and showed increased serum IL-1beta levels. In addition, BMDMs isolated from BPOZ-2 KO mice showed increased IL-1beta production in response to NLRP3 stimuli. Mechanistically, BPOZ-2 interacted with NLRP3 and mediated its degradation by recruiting Cullin 3. In particular, the expression of BPOZ-2 was significantly reduced in lung tissues from mice infected with SARS-CoV-2 and in cells overexpressing SARS-2-N. Importantly, proinflammatory responses triggered by the SARS-2-N were significantly blocked by BPOZ-2 reintroduction. Thus, we concluded that BPOZ-2 is a negative regulator of the NLPR3 inflammasome that likely contributes to SARS-CoV-2-induced hyperinflammation. CI - Copyright (c) 2023 Li, Lin, Fan, Huang, Zhang, Tai, Fang, Li, Zhao, Wang, Zhou, Wan, Wu, Zhong, Wei and Yang. FAU - Li, Jingfei AU - Li J AD - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China. FAU - Lin, Haotian AU - Lin H AD - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China. FAU - Fan, Tinghui AU - Fan T AD - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China. FAU - Huang, Linfei AU - Huang L AD - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China. FAU - Zhang, Xinyong AU - Zhang X AD - Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, China. FAU - Tai, Yanhong AU - Tai Y AD - Department of Pathology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China. FAU - Fang, Yi AU - Fang Y AD - Department of Endocrinology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China. FAU - Li, Qihong AU - Li Q AD - Department of Stomatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China. FAU - Zhao, Ruzhou AU - Zhao R AD - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China. FAU - Wang, Penghao AU - Wang P AD - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China. FAU - Zhou, Li AU - Zhou L AD - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China. FAU - Wan, Luming AU - Wan L AD - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China. FAU - Wu, Yuhua AU - Wu Y AD - Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, China. FAU - Zhong, Hui AU - Zhong H AD - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China. FAU - Wei, Congwen AU - Wei C AD - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China. FAU - Yang, Xiaopan AU - Yang X AD - Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230302 PL - Switzerland TA - Front Cell Infect Microbiol JT - Frontiers in cellular and infection microbiology JID - 101585359 RN - 0 (Cullin Proteins) RN - 0 (Inflammasomes) RN - 0 (Lipopolysaccharides) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Abtb2 protein, mouse) RN - 0 (Nuclear Proteins) SB - IM MH - Animals MH - Mice MH - *Acute Lung Injury/metabolism MH - *COVID-19 MH - Cullin Proteins MH - Inflammasomes/metabolism MH - Lipopolysaccharides/pharmacology MH - Mice, Inbred C57BL MH - *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism MH - SARS-CoV-2/metabolism MH - *Shock, Septic MH - *Nuclear Proteins/genetics/metabolism PMC - PMC10019892 OTO - NOTNLM OT - BPOZ-2 OT - NLPR3 OT - SARS-CoV-2 OT - hyperinflammation OT - inflammasome COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/03/21 06:00 MHDA- 2023/03/22 06:00 PMCR- 2023/03/02 CRDT- 2023/03/20 03:53 PHST- 2022/12/30 00:00 [received] PHST- 2023/02/09 00:00 [accepted] PHST- 2023/03/20 03:53 [entrez] PHST- 2023/03/21 06:00 [pubmed] PHST- 2023/03/22 06:00 [medline] PHST- 2023/03/02 00:00 [pmc-release] AID - 10.3389/fcimb.2023.1134511 [doi] PST - epublish SO - Front Cell Infect Microbiol. 2023 Mar 2;13:1134511. doi: 10.3389/fcimb.2023.1134511. eCollection 2023.