DDX19A Senses Viral RNA and Mediates NLRP3-Dependent Inflammasome Activation

Abstract

The NLRP3 inflammasome plays a major role in innate immune responses by activating caspase-1, resulting in secretion of IL-1β and inflammatory pathologic responses. Viral RNA can induce NLRP3 inflammasome activation. However, none of the components of NLRP3 inflammasome has the ability to bind viral RNA. Therefore, it had been proposed that there might have been some unidentified cytosolic RNA sensors that could bind viral RNA and NLRP3 to initiate NLRP3 inflammasome activation. In this study, DDX19A, a member of the DEAD/H-box protein family, was identified as a novel component of NLRP3 inflammasome using arterivirus infection as a model. We found that DDX19A interacted with viral RNA and NLRP3. Knockdown of DDX19A expression efficiently inhibited procaspase-1 cleavage and IL-1β secretion in porcine reproductive and respiration syndrome virus (PRRSV)–infected or PRRSV RNA-stimulated primary porcine alveolar macrophages. Overall, DDX19A was identified as a novel cytosolic RNA sensor that bridged PRRSV RNA and NLRP3 to activate NLRP3 inflammasome.

NLRP3 Inflammasome—A Key Player in Antiviral Responses

“…2 ′ ,5 ′ -oligoadenylate (2-5A) synthetase (OAS) recognizes dsRNA from some viruses, such as IAV and VSV, and promotes the cleavage thereof by endoribonuclease RNase L; the cleaved nucleic acids then be detected by DHX33 (35). Furthermore, DDX19A, another DExD/H-box RNA helicase family member, senses porcine reproductive and respiration syndrome virus (PRRSV) and promotes NLRP3 inflammasome activation (36).…”

The inflammasome: an emerging therapeutic oncotarget for cancer prevention

“…Various bacterial pathogens can secret pore-forming toxins (e.g., nigericin from Streptomyces hygroscopicus , listeriolysin O from Listeria monocytogenes , pneumolysin from Streptococcus pneumoniiae , alpha-hemolysin from Escherichia coli ) and subsequently activate the NLRP3 inflammasome by increasing potassium efflux [70-76]. In addition, bacterial and viral RNA is also reported to be an initial factor contributing to NLRP3 inflammasome assembly [77]. Moreover, extracellular ATP released from phagocytosed dying cells acts on purinergic receptor, P2×7 and induces pannexin-1 (PANX1) channels to promote potassium efflux and results in NLRP3 activation [78-80].…”

Molecular and Cellular Mechanisms for PRRSV Pathogenesis and Host Response to Infection

“…PRRSV can activate the inflammasomes in PAMs, and PRRSV induces IL-1β production dependent on TLR4/MyD88/NF-κB signaling pathway and the NLRP3 inflammasome (Bi et al, 2014). Viral RNA can be sensed by cytosolic RNA sensor DDX19A to activate NLRP3 inflammasome (Li et al, 2015a). Viral proteins can also regulate NLRP3 inflammation.…”