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

TLDR

The innate immune system releases pro‑inflammatory cytokines such as IL‑1β via the NLRP3 inflammasome, and the stimulator of interferon genes (STING) plays essential roles in pathogen‑induced innate responses. The study aims to uncover how STING regulates NLRP3 inflammasome activation, IL‑1β secretion, and inflammation in human cells, mouse primary cells, and mice. STING promotes NLRP3 inflammasome activation by recruiting NLRP3 to the endoplasmic reticulum and by deubiquitinating NLRP3, reducing K48‑ and K63‑linked polyubiquitination. STING binds NLRP3 during HSV‑1 infection and cytosolic DNA stimulation, activating the inflammasome, and the cGAS‑STING‑NLRP3 axis is essential for host defense against HSV‑1.

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.