A new paper by Calderon and Conn demonstrates that conformational plasticity determines the ability of one RNA sequence to bind to and activate the pattern recognition receptor OAS1/RNase L. In identifying a novel mode through which the immune response is naturally controlled, this finding opens new avenues toward developing approaches for the management of a wide range of viral infections.
Oligoadenylate synthetase (OAS) protein family is the major interferon (IFN)-stimulated genes responsible for the activation of RNase L pathway upon viral infection.
Host cells develop the OAS/RNase L [2'-5'-oligoadenylate synthetase (OAS)/ribonuclease L] system to degrade cellular and viral RNA, and/or the OASL/RIG-I (2'-5'-OAS like/retinoic acid inducible protein I) system to enhance RIG-I-mediated IFN induction, thus providing the first line of defense against viral infection.
OAS is activated by dsRNA and IFNs to produce 2' -5' oligoadenylates, which are activators of RNase L. This enzyme degrades viral and cellular RNAs, thus restricting viral infection.
Although all three enzymatically active OAS proteins in humans--OAS1, OAS2, and OAS3--synthesize 2-5A upon binding dsRNA, it is unclear which are responsible for RNase L activation during viral infection.
One of the key antiviral factors induced by IFNs, 2'-5' oligoadenylate synthase (OAS), is a well-known molecule that regulates the early phase of viral infection by degrading viral RNA in combination with RNase L, resulting in the inhibition of viral replication.
Our results demonstrate a novel role of RNase L generated small RNAs in cross-talk between autophagy and apoptosis that impacts the fate of cells during viral infections and cancer.
Thus, polymorphisms at the RNASEL gene do not seem to influence the susceptibility to common viral infections or conditions potentially of viral etiology.
For example, small RNA cleavage products produced by RNase L during viral infections can signal to the retinoic acid-inducible-I like receptors to amplify and perpetuate signaling to the IFN-β gene.
Thus, efficient apoptosis in response to viral dsRNA results from the co-operation of the two major apical caspases (8 and 9) and the dsRNA-activated protein kinase R (PKR)/ribonuclease L (RNase L) system that is essential for the inhibition of protein synthesis in response to viral infection.
Because 2-5A and RNase L participate in defenses against viral infections and prostate cancer, our findings have implications for basic cellular mechanisms that control major pathogenic processes.