Mitochondrial protein mitofusin 2 is required for NLRP3 inflammasome activation after RNA virus infection

Abstract

Nod-like receptor family, pyrin domain-containing 3 (NLRP3), is involved in the early stages of the inflammatory response by sensing cellular damage or distress due to viral or bacterial infection. Activation of NLRP3 triggers its assembly into a multimolecular protein complex, termed "NLRP3 inflammasome." This event leads to the activation of the downstream molecule caspase-1 that cleaves the precursor forms of proinflammatory cytokines, such as interleukin 1 beta (IL-1β) and IL-18, and initiates the immune response. Recent studies indicate that the reactive oxygen species produced by mitochondrial respiration is critical for the activation of the NLRP3 inflammasome by monosodium urate, alum, and ATP. However, the precise mechanism by which RNA viruses activate the NLRP3 inflammasome is not well understood. Here, we show that loss of mitochondrial membrane potential [ΔΨ(m)] dramatically reduced IL-1β secretion after infection with influenza, measles, or encephalomyocarditis virus (EMCV). Reduced IL-1β secretion was also observed following overexpression of the mitochondrial inner membrane protein, uncoupling protein-2, which induces mitochondrial proton leakage and dissipates ΔΨ(m). ΔΨ(m) was required for association between the NLRP3 and mitofusin 2, a mediator of mitochondrial fusion, after infection with influenza virus or EMCV. Importantly, the knockdown of mitofusin 2 significantly reduced the secretion of IL-1β after infection with influenza virus or EMCV. Our results provide insight into the roles of mitochondria in NLRP3 inflammasome activation. mitochondria | innate immunity

Intracellular ATP Decrease Mediates NLRP3 Inflammasome Activation upon Nigericin and Crystal Stimulation

“…As several studies have demonstrated the important role of mitochondria in the regulation of IL-1b secretion (17)(18)(19)(20), we examined the change in Dcm, an indicator of mitochondrial function. Reduction of iATP levels significantly depolarized Dcm, although not reaching the maximal depolarization obtained with the positive control CCCP, an uncoupler of oxidative phosphorylation (Fig.…”

Molecular mechanisms regulating NLRP3 inflammasome activation

“…115 Moreover, the interaction of NLRP3 with mitofusin 2, a mediator of mitochondrial fusion, is required for NLRP3 inflammasome activation after infection with RNA viruses, including influenza and encephalomyocarditis virus. 116 A specific role for the serine-threonine kinases RIP1 (RIPK1) and RIP3 (RIPK3) has been recently reported recently in the activation of the NLRP3 inflammasome complex during infection with RNA viruses. 117 RNA viral infection triggers the assembly of the RIP1-RIP3 complex, which, in turn, activates the GTPase DRP1 and its translocation to mitochondria, resulting in mitochondrial damage and NLRP3 inflammasome activation.…”

Inflammasome Priming in Sterile Inflammatory Disease

“…An important distinction however is that activation of NLRP3 may actually be related to mitochondrial membrane potential [16,17] , while mROS production itself may in fact influence priming of NLRP3 [18] .…”