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

Journal Article: Nature CommunicationsYear Published: (2018) Volume Number: 9, Article Number: 1820


Koliopoulos, Marios G.; Lethier, Mathilde; van der Veen, Annemarthe G.; Haubrich, Kevin; Hennig, Janosch; Kowalinski, Eva; Stevens, Rebecca V.; Martin, Stephen R.; Reis e Sousa, Caetano; Cusack, Stephen; Rittinger, Katrin

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.