An E1–E2 fusion protein primes antiviral immune signalling in bacteria

Hannah E. Ledvina, Qiaozhen Ye, Yajie Gu, Ashley E. Sullivan, Yun Quan, Rebecca K. Lau, Huilin Zhou, Kevin D. Corbett () and Aaron T. Whiteley ()
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Hannah E. Ledvina: University of Colorado Boulder
Qiaozhen Ye: University of California, San Diego
Yajie Gu: University of California, San Diego
Ashley E. Sullivan: University of Colorado Boulder
Yun Quan: University of California, San Diego
Rebecca K. Lau: University of California, San Diego
Huilin Zhou: University of California, San Diego
Kevin D. Corbett: University of California, San Diego
Aaron T. Whiteley: University of Colorado Boulder

Nature, 2023, vol. 616, issue 7956, 319-325

Abstract: Abstract In all organisms, innate immune pathways sense infection and rapidly activate potent immune responses while avoiding inappropriate activation (autoimmunity). In humans, the innate immune receptor cyclic GMP–AMP synthase (cGAS) detects viral infection to produce the nucleotide second messenger cyclic GMP–AMP (cGAMP), which initiates stimulator of interferon genes (STING)-dependent antiviral signalling1. Bacteria encode evolutionary predecessors of cGAS called cGAS/DncV-like nucleotidyltransferases2 (CD-NTases), which detect bacteriophage infection and produce diverse nucleotide second messengers3. How bacterial CD-NTase activation is controlled remains unknown. Here we show that CD-NTase-associated protein 2 (Cap2) primes bacterial CD-NTases for activation through a ubiquitin transferase-like mechanism. A cryo-electron microscopy structure of the Cap2–CD-NTase complex reveals Cap2 as an all-in-one ubiquitin transferase-like protein, with distinct domains resembling eukaryotic E1 and E2 proteins. The structure captures a reactive-intermediate state with the CD-NTase C terminus positioned in the Cap2 E1 active site and conjugated to AMP. Cap2 conjugates the CD-NTase C terminus to a target molecule that primes the CD-NTase for increased cGAMP production. We further demonstrate that a specific endopeptidase, Cap3, balances Cap2 activity by cleaving CD-NTase–target conjugates. Our data demonstrate that bacteria control immune signalling using an ancient, minimized ubiquitin transferase-like system and provide insight into the evolution of the E1 and E2 machinery across domains of life.

Date: 2023
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DOI: 10.1038/s41586-022-05647-4

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