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

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

doi:10.1038/s41467-018-04214-8

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

Nat Commun. 2018 May 8;9(1):1820. doi: 10.1038/s41467-018-04214-8.

Affiliations

¹ Molecular Structure of Cell Signalling Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
² European Molecular Biology Laboratory, 71 Avenue des Martyrs, 38042, Grenoble, Cedex 9, France.
³ Immunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
⁴ Structural and Computational Biology Unit, EMBL Heidelberg, Meyerhofstraße 1, 69117, Heidelberg, Germany.
⁵ Structural Biology Science Technology Platform, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
⁶ Molecular Structure of Cell Signalling Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Cells, Cultured
DEAD Box Protein 58 / immunology
HEK293 Cells
Humans
Interferons / biosynthesis
Protein Binding
Protein Domains
Protein Multimerization
RNA, Viral / immunology
Receptors, Immunologic
Signal Transduction
Transcription Factors / antagonists & inhibitors*
Transcription Factors / chemistry
Transcription Factors / immunology*
Tripartite Motif Proteins / antagonists & inhibitors*
Tripartite Motif Proteins / chemistry
Tripartite Motif Proteins / immunology*
Ubiquitin-Protein Ligases / antagonists & inhibitors*
Ubiquitin-Protein Ligases / chemistry
Ubiquitin-Protein Ligases / immunology*
Ubiquitination
Viral Nonstructural Proteins / chemistry*
Viral Nonstructural Proteins / immunology*

Substances

INS1 protein, influenza virus
RNA, Viral
Receptors, Immunologic
Transcription Factors
Tripartite Motif Proteins
Viral Nonstructural Proteins
Interferons
TRIM25 protein, human
Ubiquitin-Protein Ligases
RIGI protein, human
DEAD Box Protein 58

Grants and funding

WT_/Wellcome Trust/United Kingdom