Defining the RNA signatures detected by the innate immune sensor 2’-5’-oligoadenylate synthetase 1 (OAS1) Restricted; Files & ToC

Schwartz, Samantha (Spring 2021)

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The innate immune system is a broad set of critical intracellular and extracellular processes that limit pathogen infectivity. To provide its essential first line of defenses, the innate immune system must identify and respond to foreign molecules. The 2’-5’-oligoadenylate synthetase (OAS) family of enzymes are important innate immune sensors of cytosolic double-stranded RNA (dsRNA), a potent signal and hallmark of viral infection. Defective or misregulated innate immune activity can cause increased persistence of and susceptibility to viral infection and human diseases, such as interferonopathies. My dissertation research investigates how specific molecular signatures within dsRNA molecules regulate OAS1 activity.

Structural studies previously revealed that dsRNA binding induces allosteric changes in OAS1 that reorganize its catalytic site and drive synthesis of 2’-5’-oligoadenylates from ATP. However, we still understand relatively little about how specific features of the dsRNA contribute to the level of OAS1 activation. I used a “simple” 18 bp dsRNA containing two copies of a previously identified OAS1 activation consensus sequence (WWN9WG, where W is A or U, and N is any nucleotide) to identify and assess the contributions of specific dsRNA features required for potent OAS1 activation. Biochemical studies coupled with cell-based assays and computational modeling reveal that the 18 bp dsRNA contains two competing OAS1 binding sites with remarkably different capacities to activate the protein in a context-dependent manner. The dsRNA binding register was dictated by the position of the consensus sequence(s) and only when optimally positioned was potency of other RNA activating motifs observed. A new role was also identified for the non-conserved (N9) nucleotides of the activation consensus in defining the dsRNA shape and flexibility important for OAS1 binding and recognition. The results indicate that OAS1 is unexpectedly sensitive to sequence, but also that the relative placement and organization of activating motifs is as critical as the sequences themselves. These studies define the molecular mechanism(s) that control OAS1 regulation by dsRNA and may reveal insight into viral evasion of the OAS1/RNase L pathway or avenues to new effective therapeutic strategies.

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