Phage anti-CBASS protein simultaneously sequesters cyclic trinucleotides and dinucleotides

Xueli Cao; Yu Xiao; Erin Huiting; Xujun Cao; Dong Li; Jie Ren; Iana Fedorova; Hao Wang; Linlin Guan; Yu Wang; Lingyin Li; Joseph Bondy-Denomy; Yue Feng

doi:10.1016/j.molcel.2023.11.026

Phage anti-CBASS protein simultaneously sequesters cyclic trinucleotides and dinucleotides

Mol Cell. 2024 Jan 18;84(2):375-385.e7. doi: 10.1016/j.molcel.2023.11.026. Epub 2023 Dec 15.

Authors

Xueli Cao¹, Yu Xiao², Erin Huiting³, Xujun Cao⁴, Dong Li¹, Jie Ren⁵, Iana Fedorova³, Hao Wang¹, Linlin Guan¹, Yu Wang¹, Lingyin Li⁶, Joseph Bondy-Denomy⁷, Yue Feng⁸

Affiliations

¹ Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
² Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing 100084, China.
³ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
⁴ Department of Chemistry, Stanford University, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University, Stanford, CA 94305, USA; Sarafan ChEM-H Institute, Stanford University, Stanford, CA 94305, USA; Arc Institute, Palo Alto, CA 94304, USA.
⁵ State Key Laboratory for Biology of Plant Diseases and Insect Pests, Ministry of Agriculture, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100081, China.
⁶ Department of Biochemistry, Stanford University, Stanford, CA 94305, USA; Sarafan ChEM-H Institute, Stanford University, Stanford, CA 94305, USA; Arc Institute, Palo Alto, CA 94304, USA.
⁷ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Innovative Genomics Institute, Berkeley, CA 94720, USA. Electronic address: [email protected].
⁸ Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China. Electronic address: [email protected].

Abstract

Cyclic-oligonucleotide-based anti-phage signaling system (CBASS) is a common immune system that uses cyclic oligonucleotide signals to limit phage replication. In turn, phages encode anti-CBASS (Acb) proteins such as Acb2, which can sequester some cyclic dinucleotides (CDNs) and limit downstream effector activation. Here, we identified that Acb2 sequesters many CDNs produced by CBASS systems and inhibits stimulator of interferon genes (STING) activity in human cells. Surprisingly, the Acb2 hexamer also binds with high affinity to CBASS cyclic trinucleotides (CTNs) 3'3'3'-cyclic AMP-AMP-AMP and 3'3'3'-cAAG at a distinct site from CDNs. One Acb2 hexamer can simultaneously bind two CTNs and three CDNs. Phage-encoded Acb2 provides protection from type III-C CBASS that uses cA₃ signaling molecules. Moreover, phylogenetic analysis of >2,000 Acb2 homologs encoded by diverse phages and prophages revealed that most are expected to bind both CTNs and CDNs. Altogether, Acb2 sequesters nearly all known CBASS signaling molecules through two distinct binding pockets and therefore serves as a broad-spectrum inhibitor of cGAS-based immunity.

Keywords: CBASS; anti-CBASS protein; cyclic dinucleotides; cyclic trinucleotides; sponge protein.

MeSH terms

Bacteriophages* / genetics
Bacteriophages* / metabolism
Cyclic AMP
Humans
Nucleotides, Cyclic* / metabolism
Oligonucleotides
Phylogeny

Substances

Nucleotides, Cyclic
Cyclic AMP
Oligonucleotides

Abstract

MeSH terms

Substances

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