Viruses inhibit TIR gcADPR signalling to overcome bacterial defence

Azita Leavitt, Erez Yirmiya, Gil Amitai, Allen Lu, Jeremy Garb, Ehud Herbst, Benjamin R. Morehouse, Samuel J. Hobbs, Sadie P. Antine, Zhen-Yu J. Sun, Philip J. Kranzusch () and Rotem Sorek ()
Additional contact information
Azita Leavitt: Weizmann Institute of Science
Erez Yirmiya: Weizmann Institute of Science
Gil Amitai: Weizmann Institute of Science
Allen Lu: Harvard Medical School
Jeremy Garb: Weizmann Institute of Science
Ehud Herbst: Weizmann Institute of Science
Benjamin R. Morehouse: Harvard Medical School
Samuel J. Hobbs: Harvard Medical School
Sadie P. Antine: Harvard Medical School
Zhen-Yu J. Sun: Dana-Farber Cancer Institute
Philip J. Kranzusch: Harvard Medical School
Rotem Sorek: Weizmann Institute of Science

Nature, 2022, vol. 611, issue 7935, 326-331

Abstract: Abstract The Toll/interleukin-1 receptor (TIR) domain is a key component of immune receptors that identify pathogen invasion in bacteria, plants and animals1–3. In the bacterial antiphage system Thoeris, as well as in plants, recognition of infection stimulates TIR domains to produce an immune signalling molecule whose molecular structure remains elusive. This molecule binds and activates the Thoeris immune effector, which then executes the immune function1. We identified a large family of phage-encoded proteins, denoted here as Thoeris anti-defence 1 (Tad1), that inhibit Thoeris immunity. We found that Tad1 proteins are ‘sponges’ that bind and sequester the immune signalling molecule produced by TIR-domain proteins, thus decoupling phage sensing from immune effector activation and rendering Thoeris inactive. Tad1 can also efficiently sequester molecules derived from a plant TIR-domain protein, and a high-resolution crystal structure of Tad1 bound to a plant-derived molecule showed a unique chemical structure of 1 ′′–2′ glycocyclic ADPR (gcADPR). Our data furthermore suggest that Thoeris TIR proteins produce a closely related molecule, 1′′–3′ gcADPR, which activates ThsA an order of magnitude more efficiently than the plant-derived 1′′–2′ gcADPR. Our results define the chemical structure of a central immune signalling molecule and show a new mode of action by which pathogens can suppress host immunity.

Date: 2022
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DOI: 10.1038/s41586-022-05375-9

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