RNase L and the NLRP3-inflammasome: An old merchant in a new trade

The type I/III interferon (IFN)-inducible 2′-5′- oligoadenylate synthetase (OAS)/endoribonuclease L (RNase L) is a classical innate immune pathway that has been implicated in antiviral and antibacterial defense and also in hereditary prostate cancer. The OAS/RNase L pathway is activated when OAS senses double-stranded RNA and catalyzes the synthesis of 2′-5′ linked oligodenylates (2-5A) from ATP. 2-5A then binds and activates RNase L, resulting cleavage of single-stranded RNAs. RNase L cleavage products are capable of activating RIG-like receptors such as RIG-I and MDA5 that leads to IFN-β expression during viral infection. Our recent findings suggest that beside the RLR pathway, RNase L cleavage products can also activate the NLRP3-inflammasome pathway, which requires DHX33 (DExD/H-box helicase) and the mitochondrial adaptor protein MAVS. Here we discuss this newly identified role of OAS-RNase L pathway in regulation of inflammasome signaling as an alternative antimicrobial mechanism that has potential as a target for development of new broad-spectrum antimicrobial and anti-inflammatory therapies.