Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition
journal contributionposted on 20.08.2020, 16:44 by Marios G Koliopoulos, Mathilde Lethier, Annemarthe G van der Veen, Kevin Haubrich, Janosch Hennig, Eva Kowalinski, Rebecca V Stevens, Stephen R Martin, Caetano Reis e Sousa, Stephen Cusack, Katrin Rittinger
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.
Amino Acid SequenceCells, CulturedDEAD Box Protein 58HEK293 CellsHumansInterferonsProtein BindingProtein DomainsProtein MultimerizationRNA, ViralSignal TransductionTranscription FactorsTripartite Motif ProteinsUbiquitin-Protein LigasesUbiquitinationViral Nonstructural ProteinsRittinger FC001142Reis e Sousa FC001136SBPRT-ack