OAS proteins and cGAS: unifying concepts in sensing and responding to cytosolic nucleic acids - PubMed (original) (raw)

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

Veit Hornung et al. Nat Rev Immunol. 2014 Aug.

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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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1

Figure 1. Simplified schematic comparison of the OAS1–RNase L and cGAS–STING axes in innate immune signalling and antiviral defence.

Upon double-stranded RNA (dsRNA) binding, oligoadenylate synthase (OAS) enzymes undergo a conformational switch, which results in their catalytic activity — that is, the synthesis of 2′–5′-linked oligoadenylates using ATP as a substrate. 2′–5′-linked oligoadenylates subsequently act as second messenger molecules by activating the latent endoribonuclease RNase L in the cytoplasm. RNase L then forms a crossed dimer and degrades RNA that is of both cellular and viral origin, leading to the inhibition of viral propagation. On the other hand, cyclic GMP–AMP (cGAMP) synthase (cGAS) is activated by cytosolic B-form dsDNA to synthesize the non-canonical cyclic dinucleotide (CDN) cGAMP(2′–5′) as its second messenger molecule (using the substrates ATP and GTP). cGAMP(2′–5′) binds to and activates the endoplasmic reticulum (ER)-resident receptor stimulator of interferon genes (STING), which subsequently translocates to a perinuclear Golgi compartment where it obtains its signalling-competent state. This results in the activation of transcription factors that initiate antiviral and pro-inflammatory gene expression. At the same time, cGAMP(2′–5′) can also diffuse through gap junctions to initiate antiviral activity in bystander cells. In addition to its role in sensing the endogenous second messenger molecule cGAMP(2′–5′), STING responds to exogenous CDNs that are derived from prokaryotes (not shown). IκB, inhibitor of NF-κB; IKK, IκB kinase complex; IRF3, interferon-regulatory factor 3; NF-κB, nuclear factor-κB; TBK1, TANK-binding kinase 1. PowerPoint slide

Figure 2

Figure 2. Structures of OAS1 and cGAS.

a | Two views of 2′–5′-oligoadenylate synthase 1 (OAS1) in complex with double-stranded RNA (dsRNA). b | Two views of the cyclic GMP–AMP (cGAMP) synthase (cGAS) dimer (light and dark blue) in complex with dsDNA. c | Close up comparison of cGAS in the apo form (grey) and DNA-bound form (blue). DNA binds to the platform at site A and induces a structural switch in the spine helix (indicated by arrows) and active site loops, thereby facilitating ATP and GTP binding and catalysis. ZT, zinc thumb. PowerPoint slide

Figure 3

Figure 3. Unified mechanism of nucleotidyl transfer by cGAS and OAS1 proteins.

a | The mechanism for two-step nucleotidyl transfer in the formation of cyclic GMP–AMP (cGAMP) by cGAMP synthase (cGAS). Selected catalytically important residues, as well as two magnesium ions, are indicated. In particular, Glu225 and Asp227 bind the two magnesium ions that are crucial to orient and activate the donor triphosphate moiety. Asp319 polarizes the attacking 2′-OH, and Tyr436 and Glu383 bind base and ribose, respectively. After the first catalytic step, the pppGp(2′–5′)A intermediate needs to dissociate and rebind in reverse order (swap) for the second catalytic step. Human cGAS numbering is used for the amino acid residues shown. b | Nucleotidyl transfer 1 by oligoadenylate synthase 1 (OAS1) is similar to that of cGAS. Instead of a nucleotide swap, as observed in cGAS, the product of nucleotidyl transfer 1 rebinds to the acceptor site only. In the beginning, the acceptor is ATP (in ATP acceptor, 'R' denotes diphosphate group), whereas in subsequent steps, during chain elongation, the acceptor is pppAp(2′–5′)A and longer 2′–5′-linked oligoadenylates ('R' denotes pppAp(2′–5′)A and longer chains). Human OAS1 numbering is used for the amino acid residues shown. PowerPoint slide

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