STING promotes NLRP3 localization in ER and facilitates NLRP3 deubiquitination to activate the inflammasome upon HSV-1 infection

Wenbiao Wang; Dingwen Hu; Caifeng Wu; Yuqian Feng; Aixin Li; Weiyong Liu; Yingchong Wang; Keli Chen; Mingfu Tian; Feng Xiao; Qi Zhang; Muhammad Adnan Shereen; Weijie Chen; Pan Pan; Pin Wan; Kailang Wu; Jianguo Wu

doi:10.1371/journal.ppat.1008335

STING promotes NLRP3 localization in ER and facilitates NLRP3 deubiquitination to activate the inflammasome upon HSV-1 infection

PLoS Pathog. 2020 Mar 18;16(3):e1008335. doi: 10.1371/journal.ppat.1008335. eCollection 2020 Mar.

Authors

Wenbiao Wang¹, Dingwen Hu², Caifeng Wu¹, Yuqian Feng¹, Aixin Li², Weiyong Liu², Yingchong Wang², Keli Chen², Mingfu Tian², Feng Xiao², Qi Zhang², Muhammad Adnan Shereen², Weijie Chen¹, Pan Pan¹, Pin Wan¹, Kailang Wu², Jianguo Wu^{1

2}

Affiliations

¹ Guangdong Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, China.
² State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Endoplasmic Reticulum / immunology*
Endoplasmic Reticulum / metabolism
Herpes Simplex / genetics
Herpes Simplex / immunology*
Herpes Simplex / metabolism
Herpes Simplex / virology
Herpesvirus 1, Human / genetics
Herpesvirus 1, Human / physiology
Humans
Immunity, Innate
Inflammasomes / genetics
Inflammasomes / immunology*
Inflammasomes / metabolism
Macrophages / immunology
Membrane Proteins / genetics
Membrane Proteins / immunology
Membrane Proteins / metabolism*
Mice
Mice, Inbred C57BL
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / immunology*
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Protein Binding
Protein Transport

Substances

Inflammasomes
Membrane Proteins
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Sting1 protein, mouse

Grants and funding

This work was supported by the National Natural Science Foundation of China (81730061 and 81471942), the National Health and Family Planning Commission of China (National Mega Project on Major Infectious Disease Prevention) (2017ZX10103005 and 2017ZX10202201), Guangdong Province “Pearl River Talent Plan” Innovation and Entrepreneurship Team Project (2017ZT07Y580), and Postdoctoral Science Foundation of China (2018T110923). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.