Abstract
Activation of NLRP3 inflammasome is important for effective host defense against invading pathogen. Together with apoptosis-associated speck-like protein containing CARD domain (ASC), NLRP3 induces the cleavage of caspase-1 to facilitate the maturation of interleukin-1beta (IL-1β), an important pro-inflammatory cytokine. IL-1β subsequently plays critical roles in inflammatory responses by activating immune cells and inducing many secondary pro-inflammatory cytokines. Although the role of NLRP3 inflammasome in immune response is well defined, the mechanism underlying its assembly modulated by pathogen infection remains largely unknown. Here, we identified a novel mechanism by which enterovirus 71 (EV71) facilitates the assembly of NLRP3 inflammasome. Our results show that EV71 induces production and secretion of IL-1β in macrophages and peripheral blood mononuclear cells (PBMCs) through activation of NLRP3 inflammasome. EV71 replication and protein synthesis are required for NLRP3-mediated activation of IL-1β. Interestingly, EV71 3D protein, a RNA-dependent RNA polymerase (RdRp) was found to stimulate the activation of NLRP3 inflammasome, the cleavage of pro-caspase-1, and the release of IL-1β through direct binding to NLRP3. More importantly, 3D interacts with NLRP3 to facilitate the assembly of inflammasome complex by forming a 3D-NLRP3-ASC ring-like structure, resulting in the activation of IL-1β. These findings demonstrate a new role of 3D as an important player in the activation of inflammatory response, and identify a novel mechanism underlying the modulation of inflammasome assembly and function induced by pathogen invasion.
Highlights
The innate immune system is a highly conserved signaling network important for protection of the infected host and clearance of the invading pathogen [1]
An important part of the innate immune response is the activation of NLR family PYRIN domain containing-3 (NLRP3) inflammasome, which is induced upon exposure to pathogens
We demonstrate that enterovirus 71 (EV71) 3D RNA polymerase activates NLRP3 inflammasome by binding to NLRP3
Summary
The innate immune system is a highly conserved signaling network important for protection of the infected host and clearance of the invading pathogen [1]. An important part of the innate immune response is the activation of inflammasome, a cytosolic complex of proteins that activates caspase-1 (Casp-1) to produce the pro-inflammatory cytokine interleukin-1beta (IL-1β) [6]. NLRP3 oligomerizes through homotypic interactions between NACHT domains following the detection of pathogen infection or cellular stress. NLRP3 inflammasome is activated upon exposure to pathogens, including bacteria (Listeria monocytogenes and Staphylococcus aureus) [8] and viruses (Sendai virus, adenovirus and influenza virus) [9] [10], by host-derived molecules, such as extracellular glucose [11], extracellular ATP [12], and hyaluronan [13], and detects signs of metabolic stress and environmental irritants [7]. IL-1β plays an important role in inflammatory response by recruitment and activation of immune cells as well as production of secondary pro-inflammatory cytokines [15]
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