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Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition

Author

Listed:
  • Marios G. Koliopoulos

    (The Francis Crick Institute)

  • Mathilde Lethier

    (European Molecular Biology Laboratory)

  • Annemarthe G. Veen

    (The Francis Crick Institute)

  • Kevin Haubrich

    (EMBL Heidelberg)

  • Janosch Hennig

    (EMBL Heidelberg)

  • Eva Kowalinski

    (European Molecular Biology Laboratory)

  • Rebecca V. Stevens

    (The Francis Crick Institute)

  • Stephen R. Martin

    (The Francis Crick Institute)

  • Caetano Reis e Sousa

    (The Francis Crick Institute)

  • Stephen Cusack

    (European Molecular Biology Laboratory)

  • Katrin Rittinger

    (The Francis Crick Institute)

Abstract

RIG-I is a viral RNA sensor that induces the production of type I interferon (IFN) in response to infection with a variety of viruses. Modification of RIG-I with K63-linked poly-ubiquitin chains, synthesised by TRIM25, is crucial for activation of the RIG-I/MAVS signalling pathway. TRIM25 activity is targeted by influenza A virus non-structural protein 1 (NS1) to suppress IFN production and prevent an efficient host immune response. Here we present structures of the human TRIM25 coiled-coil-PRYSPRY module and of complexes between the TRIM25 coiled-coil domain and NS1. These structures show that binding of NS1 interferes with the correct positioning of the PRYSPRY domain of TRIM25 required for substrate ubiquitination and provide a mechanistic explanation for how NS1 suppresses RIG-I ubiquitination and hence downstream signalling. In contrast, the formation of unanchored K63-linked poly-ubiquitin chains is unchanged by NS1 binding, indicating that RING dimerisation of TRIM25 is not affected by NS1.

Suggested Citation

  • Marios G. Koliopoulos & Mathilde Lethier & Annemarthe G. Veen & Kevin Haubrich & Janosch Hennig & Eva Kowalinski & Rebecca V. Stevens & Stephen R. Martin & Caetano Reis e Sousa & Stephen Cusack & Katr, 2018. "Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04214-8
    DOI: 10.1038/s41467-018-04214-8
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