Length dependent activation of OAS proteins by dsRNA

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  • Yinbiao Wang, School of Public Health, Xinxiang Medical University, Xinxiang, Henan, People's Republic of China; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
  • ,
  • Andreas Holleufer
  • Hans Henrik Gad
  • Rune Hartmann

The oligoadenylate synthetase (OAS) family of enzymes are interferon-inducible antiviral proteins, which synthesize the secondary messenger 2'-5'-linked oligoadenosine (2-5A) in response to viral infection. The production of 2-5As induces RNA decay within the infected cells, thereby effectively preventing further viral replication. OAS shares structural similarity as well as the enzymatic mechanism with a different antiviral protein, cyclic GMP-AMP synthase (cGAS), but OAS is activated by dsRNA whereas cGAS is activated by dsDNA. Here, we have studied the structural requirement for the dsRNA activating OAS1 and OAS3, and compared it to recent studies on cGAS. We find that both OAS1 and OAS3, like cGAS, achieve their maximum activity with dsRNA molecules that are substantial longer than what one monomer of the enzyme can interact with. One molecule of OAS1 can cover approximately 18-20 base pairs of dsRNA, which is just short of two turns of a helix. However, RNAs of this length gave a very limited activity and the length dependency was even more pronounced for OAS3. Our data suggest that the OAS enzymes evolved to recognize long dsRNA as virally derived PAMPs, and that the length of the dsRNA is an important factor in discriminating self from non-self. Several structures of OAS1 bound to short dsRNAs exist, but our data show that OAS can only achieve minimal activity with these short activators (approximately 7-8% of maximal activity) and it is thus possible that these structures do not reveal the fully activated state of the OAS enzymes.

Original languageEnglish
Article number154867
JournalCytokine
Volume126
ISSN1043-4666
DOIs
Publication statusPublished - 1 Feb 2020

    Research areas

  • Double-stranded RNA, Interferon, Oligoadenylate synthetases, Virus recognition

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