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Nat Commun. 2018 May 8;9(1):1820. doi: 10.1038/s41467-018-04214-8.
Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition.
Koliopoulos MG1, Lethier M2, van der Veen AG3, Haubrich K4, Hennig J4, Kowalinski E2, Stevens RV1, Martin SR5, Reis E Sousa C3, Cusack S2, Rittinger K6.
Author information
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.
PMID: 29739942 PMCID: PMC5940772 DOI: 10.1038/s41467-018-04214-8
Free PMC Article
Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition.
Koliopoulos MG1, Lethier M2, van der Veen AG3, Haubrich K4, Hennig J4, Kowalinski E2, Stevens RV1, Martin SR5, Reis E Sousa C3, Cusack S2, Rittinger K6.
Author information
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.
PMID: 29739942 PMCID: PMC5940772 DOI: 10.1038/s41467-018-04214-8
Free PMC Article