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OAS proteins and cGAS: unifying concepts in sensing and responding to cytosolic nucleic acids

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Abstract

Recent discoveries in the field of innate immunity have highlighted the existence of a family of nucleic acid-sensing proteins that have similar structural and functional properties. These include the well-known oligoadenylate synthase (OAS) family proteins and the recently identified OAS homologue cyclic GMP–AMP (cGAMP) synthase (cGAS). The OAS proteins and cGAS are template-independent nucleotidyltransferases that, once activated by double-stranded nucleic acids in the cytosol, produce unique classes of 2′–5′-linked second messenger molecules, which — through distinct mechanisms — have crucial antiviral functions. 2′–5′-linked oligoadenylates limit viral propagation through the activation of the enzyme RNase L, which degrades host and viral RNA, and 2′–5′-linked cGAMP activates downstream signalling pathways to induce de novo antiviral gene expression. In this Progress article, we describe the striking functional and structural similarities between OAS proteins and cGAS, and highlight their roles in antiviral immunity.

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Figure 1: Simplified schematic comparison of the OAS1–RNase L and cGAS–STING axes in innate immune signalling and antiviral defence.
Figure 2: Structures of OAS1 and cGAS.
Figure 3: Unified mechanism of nucleotidyl transfer by cGAS and OAS1 proteins.

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Acknowledgements

V.H. is supported by grants from the German Research Foundation (SFB704 and SFB670) and the European Research Council (AIM2 Inflammasome). V.H. and A.A. are members of the Cluster of Excellence ImmunoSensation. R.H. is supported by the Danish Cancer Society and the Danish council for independent research. K.-P.H. is supported by the Bavarian Research Network for Molecular Biosystems (BioSysNet; Bavarian Government), the US National Institutes of Health (grant U19U19AI083025), the Center for Integrated Protein Science Munich (CIPSM) Cluster of Excellence and by a European Research Council Advanced Grant (ATMMACHINE).

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Glossary

A-form RNA

Double-stranded RNA (dsRNA) molecules usually assemble into A-form helices within the cell. A-form helices are right-handed with 11 base pairs per helical turn and the bases are not completely perpendicular to the helical axis. In A-form dsRNA, the major groove is deep and narrow.

B-form DNA

This is the most commonly found conformation of double-stranded DNA (dsDNA) in nature. Its double helix is right-handed with 10.5 base pairs per helical turn, whereby the bases are oriented perpendicular to the helical axis. B-form dsDNA has a wide major groove and a narrow minor groove.

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Hornung, V., Hartmann, R., Ablasser, A. et al. OAS proteins and cGAS: unifying concepts in sensing and responding to cytosolic nucleic acids. Nat Rev Immunol 14, 521–528 (2014). https://doi.org/10.1038/nri3719

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