Regulation of 2’‐5’‐oligoadenylate synthetase 1 (OAS1) by small double‐stranded RNAs

Abstract

The innate immune system comprises a broad collection of critical intra‐ and extracellular processes that limit the infectivity of diverse pathogens. The 2’‐5’‐oligoadenylate synthetase (OAS) family of enzymes are important sensors of cytosolic double‐stranded RNA (dsRNA), and play a critical role in limiting viral infection by initiating signaling to halt viral replication and establish an antiviral state in the cell. Further attesting to the importance of the OAS/RNase L pathway, diverse viruses have developed numerous distinct strategies to evade the effects of OAS activation. Like other innate immune proteins, OAS must be able to accurately distinguish “self” from foreign molecules. Misregulation of the innate immune system can cause increased persistence and susceptibility to viral infection and human diseases, such as interferonopathies. Several recent studies have provided important new insights into the molecular mechanisms of OAS activation by dsRNA as well as unanticipated findings of specific RNA sequences and structural motifs that strongly enhance activation of at least one form of OAS. Although X‐ray crystal structures have given some insight into how OAS1 is activated by dsRNA, we still do not completely understand how specific features of the dsRNA contribute to the level of OAS1 activation. To address this question, we designed dsRNAs to test the impact of specific sequence changes within a strongly activating short (18 base pair) dsRNA. Remarkably, while a single point mutation on one strand resulted in complete loss of OAS1 activity, the equivalent mutation on the opposite strand led to increased OAS1 activity. Despite these stark differences in ability to activate OAS1, both variants appear to bind OAS1 with similar affinity. Given these preliminary findings, I hypothesize that dsRNAs may contain competing OAS1 binding sites with remarkably different capacities to activate the protein in a context‐dependent manner. However, the molecular signatures defining these sites as activating and non‐activating are unknown. On‐going studies to define these features will enhance our understanding of host‐pathogen interactions, such as how viruses might circumvent the OAS1/RNase L pathway by masking activating RNA motifs to evade detection.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.