Abstract

Recent studies of the SARS-CoV2 pandemic have identified the oligoadenylate synthetase (OAS)- ribonuclease L (RNase L) pathway as a key factor in determining the infection severity and in the development of multisystem inflammatory syndrome in children (MIS-C). The OAS1-3 proteins synthesise linear 2’-5’-oligoadenylates upon binding to double-stranded RNA (dsRNA), which activates RNase L, leading to the cleavage of viral and cellular RNA. However, the molecular mechanisms by which OAS proteins sense viral RNA remain poorly understood.
In this study we reveal the regulatory details of OAS2 and its specific cellular niche for  restricting viruses that induce certain membrane rearrangements. The cryo-EM structure of human OAS2 showed unexpected mechanisms of OAS2 dimer formation and auto-inhibition and enabled the identification of a novel dsRNA binding site. We also demonstrate that dimerization regulates the localization of OAS2 to the Golgi via N-terminal myristoylation, which is essential for OAS2 activity and its targeting to the sites of viral RNA replication. Finally, we identified a heterozygous OAS2 loss-of-function variant that causes paediatric autoinflammatory disease and our biochemical and cellular data explain the basis of this phenotype. In summary, we demonstrate that OAS2 is a Golgi-localized dsRNA sensor and that the correct oligomeric state and localization are key in anti-viral response and immune homeostasis.

Biosketch

Indra Bekere is a postdoctoral researcher in the School of Natural Sciences at the Technical University of Munich, supported by the DFG Walter Benjamin Programme. Since 2022, she has been investigating novel nucleotide-based second messengers in humans and the OAS–RNase L pathway in the laboratory of Prof. Carina de Oliveira Mann. Previously, she worked as a postdoctoral researcher and doctoral candidate at the University Medical Centre Hamburg-Eppendorf, Germany, in the group of Prof. Martin Aepfelbacher. Her doctoral research focused on gene expression and epigenetic changes in human macrophages during Yersinia infection, followed by postdoctoral studies on Yersinia modulation of host immune signalling.