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Published on: September 22, 2023
SARS-Coronavirus Open Reading Frame-3a drives multimodal necrotic cell death
Yuan Yue1,2, Neel R Nabar3,4, Chong-Shan Shi2
1State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
The SARS-CoV accessory protein 3a promotes necrotic cell death by interacting with Rip3 and damaging lysosomes. This process also activates caspase-1, contributing to severe lung pathology during SARS-CoV infections.
Area of Science:
- Virology
- Cellular Biology
- Pathology
Background:
- Severe lung pathology in SARS-CoV infections is not fully understood.
- The SARS-CoV accessory protein 3a (SARS 3a) is known to oligomerize and interact with cellular membranes.
Purpose of the Study:
- To investigate the role of SARS 3a in necrotic cell death pathways.
- To elucidate the mechanisms by which SARS 3a contributes to SARS-CoV pathogenesis.
Main Methods:
- Examined the interaction between SARS 3a and Receptor Interacting Protein 3 (Rip3).
- Assessed the effects of SARS 3a on lysosomal integrity and function.
- Investigated the activation of caspase-1 and NLRP3 inflammasome by SARS 3a.
Main Results:
- SARS 3a interacts with Rip3, enhancing its oligomerization and promoting necrotic cell death.
- SARS 3a insertion into lysosomal membranes causes damage and dysfunction, leading to TFEB nuclear translocation.
- SARS 3a activates caspase-1, directly or via potassium efflux, triggering NLRP3 inflammasome assembly.
Conclusions:
- Rip3-mediated oligomerization of SARS 3a drives necrotic cell death and lysosomal damage.
- SARS 3a activation of caspase-1 and NLRP3 inflammasome contributes to SARS-CoV-induced lung pathology.
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