Viral and metazoan poxins are cGAMP-specific nucleases that restrict cGAS-STING signalling

Eaglesham, James B.; Pan, Youdong; Kupper, Thomas S.; Kranzusch, Philip J.

doi:10.1038/s41586-019-0928-6

Title: Viral and metazoan poxins are cGAMP-specific nucleases that restrict cGAS-STING signalling

Journal Article · Wed Feb 06 00:00:00 EST 2019 · Nature (London)

DOI:https://doi.org/10.1038/s41586-019-0928-6· OSTI ID:1497105

Eaglesham, James B. ^[1]; Pan, Youdong ^[2]; Kupper, Thomas S. ^[3]; Kranzusch, Philip J. ^[1]

Harvard Medical School, Boston, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States); Harvard Univ., Boston, MA (United States)
Harvard Medical School, Boston, MA (United States)
Harvard Medical School, Boston, MA (United States); Dana-Farber/Brigham and Women’s Cancer Center, Boston, MA (United States)

Cytosolic DNA triggers innate immune responses through the activation of cyclic GMP–AMP synthase (cGAS) and production of the cyclic dinucleotide second messenger 2',3'-cyclic GMP–AMP (cGAMP). 2',3'-cGAMP is a potent inducer of immune signalling; however, no intracellular nucleases are known to cleave 2',3'-cGAMP and prevent the activation of the receptor stimulator of interferon genes (STING). In this work, we develop a biochemical screen to analyse 24 mammalian viruses, and identify poxvirus immune nucleases (poxins) as a family of 2',3'-cGAMP-degrading enzymes. Poxins cleave 2',3'-cGAMP to restrict STING-dependent signalling and deletion of the poxin gene (B2R) attenuates vaccinia virus replication in vivo. Crystal structures of vaccinia virus poxin in pre- and post-reactive states define the mechanism of selective 2',3'-cGAMP degradation through metal-independent cleavage of the 3'–5' bond, converting 2',3'-cGAMP into linear Gp[2'–5']Ap[3']. Poxins are conserved in mammalian poxviruses. In addition, we identify functional poxin homologues in the genomes of moths and butterflies and the baculoviruses that infect these insects. Baculovirus and insect host poxin homologues retain selective 2',3'-cGAMP degradation activity, suggesting an ancient role for poxins in cGAS–STING regulation. Our results define poxins as a family of 2',3'-cGAMP-specific nucleases and demonstrate a mechanism for how viruses evade innate immunity.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Claudia Adams Barr Program for Innovative Cancer Research; Richard and Susan Smith Family Foundation; Charles H. Hood Foundation; Cancer Research Institute; Parker Institute for Cancer Immunotherapy; National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS)

Grant/Contract Number:: R01 AI127654; R01 AR062807; AI007245; S10 RR029205; AC02-06CH11357

OSTI ID:: 1497105

Journal Information:: Nature (London), Vol. 566, Issue 7743; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 103 works

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