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

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 and Katrin Rittinger ()
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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

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04214-8

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