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.
Highlights
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
Our study suggests that the ability of non-structural protein 1 (NS1) to self-associate into higher order oligomers and crosslink different molecules of TRIM25, is important for NS1 function
These experiments showed that the ED alone binds TRIM25-CC with an affinity of 16.1 μM, whereas no binding could be detected with the RBD alone at concentrations up to 300 μM (Fig. 1c)
Summary
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. Signalling pathways mediating innate immune responses are regulated by multiple post-translational modifications to allow for a dynamic and specific host response to infection One of these is ubiquitination, where target proteins are tagged with poly-ubiquitin chains to alter their behaviour and for example change their stability, activity or promote the formation of protein–protein complexes. Tripartite motif (TRIM) family proteins are RING-type E3 ligases that play key regulatory roles in innate immune signalling pathways that lead to the induction of a type I interferon (IFN) response and production of inflammatory cytokines through activation of the IRF3 and NF-κB transcription factors[2,3]. Regardless of the covalent or non-covalent nature of the K63-linked poly-ubiquitin chains involved, the catalytic activity of TRIM25 is crucial for their synthesis and IFNβ promoter activation[21]
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