STING promotes NLRP3 localization in ER and facilitates NLRP3 deubiquitination to activate the inflammasome upon HSV-1 infection
Open Access
- 18 March 2020
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Pathogens
- Vol. 16 (3), e1008335
- https://doi.org/10.1371/journal.ppat.1008335
Abstract
One of the fundamental reactions of the innate immune responses to pathogen infection is the release of pro-inflammatory cytokines, including IL-1β, processed by the NLRP3 inflammasome. The stimulator of interferon genes (STING) has the essential roles in innate immune response against pathogen infections. Here we reveal a distinct mechanism by which STING regulates the NLRP3 inflammasome activation, IL-1β secretion, and inflammatory responses in human cell lines, mice primary cells, and mice. Interestingly, upon HSV-1 infection and cytosolic DNA stimulation, STING binds to NLRP3 and promotes the inflammasome activation through two approaches. First, STING recruits NLRP3 and facilitates NLRP3 localization in the endoplasmic reticulum, thereby facilitating the inflammasome formation. Second, STING interacts with NLRP3 and attenuates K48- and K63-linked polyubiquitination of NLRP3, thereby promoting the inflammasome activation. Collectively, we demonstrate that the cGAS-STING-NLRP3 signaling is essential for host defense against HSV-1 infection. The innate immune system is a primary host defense strategy to suppress the pathogen infections. One of the fundamental reactions of the innate immunity is the release of pro-inflammatory cytokines, including interleukine-1β (IL-1β), regulated by inflammasomes. The best-characterized inflammasomes is the NLRP3 inflammasome. STING has the essential roles in innate immune response against pathogen infections and is required for pathogen-induced inflammasome activation and IL-1β secretion. This study explores how STING regulates the NLRP3 inflammasome and reveals a distinct mechanism underlying such regulation upon herpes simplex virus type 1 (HSV-1) infection and cytosolic DNA stimulation. The authors propose that the cGAS-STING-NLRP3 axis is essential for host defense against HSV-1 infection.Keywords
Funding Information
- National Natural Science Foundation of China (81730061)
- National Natural Science Foundation of China (81471942)
- National Health and Family Planning Commission of the People's Republic of China (2017ZX10103005)
- National Health and Family Planning Commission of the People's Republic of China (2017ZX10202201)
- Guangdong Province Introduction of Innovative R&D Team (2017ZT07Y580)
- Postdoctoral Research Foundation of China (2018T110923)
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