Viruses inhibit TIR gcADPR signaling to overcome bacterial defense
Viruses inhibit TIR gcADPR signaling to overcome bacterial defense
Abstract The Toll/interleukin-1 receptor (TIR) domain is a key component of immune receptors that identify pathogen invasion in bacteria, plants, and animals. In the bacterial antiphage system Thoeris, as well as in plants, recognition of infection stimulates TIR domains to produce an immune signaling molecule whose molecular structure remained elusive. This molecule binds and activates the Thoeris immune effector, which then executes the immune function. We identified a large family of phage-encoded proteins, denoted here Thoeris anti-defense 1 (Tad1), that inhibit Thoeris immunity. We found that Tad1 proteins are “sponges” that bind and sequester the immune signaling molecule produced by TIR-domain proteins, thus decoupling phage sensing from immune effector activation and rendering Thoeris inactive. A high-resolution crystal structure of Tad1 bound to the signaling molecule revealed that its chemical structure is 1′–2′ glycocyclic ADPR (gcADPR), a unique molecule not previously described in other biological systems. Our results define the chemical structure of a central immune signaling molecule, and reveal a new mode of action by which pathogens can suppress host immunity.
Kranzusch Philip J.、Amitai Gil、Lu Allen、Garb Jeremy、Hobbs Samuel J.、Sorek Rotem、Yirmiya Erez、Morehouse Benjamin R.、Leavitt Azita
Department of Microbiology, Harvard Medical School||Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute||Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer InstituteDepartment of Molecular Genetics, Weizmann Institute of ScienceDepartment of Microbiology, Harvard Medical School||Department of Cancer Immunology and Virology, Dana-Farber Cancer InstituteDepartment of Molecular Genetics, Weizmann Institute of ScienceDepartment of Microbiology, Harvard Medical School||Department of Cancer Immunology and Virology, Dana-Farber Cancer InstituteDepartment of Molecular Genetics, Weizmann Institute of ScienceDepartment of Molecular Genetics, Weizmann Institute of ScienceDepartment of Microbiology, Harvard Medical School||Department of Cancer Immunology and Virology, Dana-Farber Cancer InstituteDepartment of Molecular Genetics, Weizmann Institute of Science
基础医学分子生物学微生物学
Kranzusch Philip J.,Amitai Gil,Lu Allen,Garb Jeremy,Hobbs Samuel J.,Sorek Rotem,Yirmiya Erez,Morehouse Benjamin R.,Leavitt Azita.Viruses inhibit TIR gcADPR signaling to overcome bacterial defense[EB/OL].(2025-03-28)[2025-06-07].https://www.biorxiv.org/content/10.1101/2022.05.03.490397.点此复制
评论