Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 16, Pages -Publisher
MDPI
DOI: 10.3390/ijms22169094
Keywords
ubiquitination; TRIM25; E3 ligase; DDX3X; DEAD-box helicase; antiviral immunity; RLR signalling; IFN; influenza; NS1
Funding
- Australian Research Council (ARC) [FT110100223]
- Australian National Health and Medical Research Council (NHMRC) [APP1157053]
- ARC Discovery Early Career Research Award [DE190100304]
- Australian Research Council [DE190100304, FT110100223] Funding Source: Australian Research Council
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The study reveals a novel interaction between TRIM25 and another protein in the RLR pathway, which cooperatively enhances IFN-beta production. Additionally, the research uncovers a new mechanism by which influenza A virus NS1 suppresses host antiviral defense.
The cytoplasmic retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) initiate interferon (IFN) production and antiviral gene expression in response to RNA virus infection. Consequently, RLR signalling is tightly regulated by both host and viral factors. Tripartite motif protein 25 (TRIM25) is an E3 ligase that ubiquitinates multiple substrates within the RLR signalling cascade, playing both ubiquitination-dependent and -independent roles in RIG-I-mediated IFN induction. However, additional regulatory roles are emerging. Here, we show a novel interaction between TRIM25 and another protein in the RLR pathway that is essential for type I IFN induction, DEAD-box helicase 3X (DDX3X). In vitro assays and knockdown studies reveal that TRIM25 ubiquitinates DDX3X at lysine 55 (K55) and that TRIM25 and DDX3X cooperatively enhance IFNB1 induction following RIG-I activation, but the latter is independent of TRIM25's catalytic activity. Furthermore, we found that the influenza A virus non-structural protein 1 (NS1) disrupts the TRIM25:DDX3X interaction, abrogating both TRIM25-mediated ubiquitination of DDX3X and cooperative activation of the IFNB1 promoter. Thus, our results reveal a new interplay between two RLR-host proteins that cooperatively enhance IFN-beta production. We also uncover a new and further mechanism by which influenza A virus NS1 suppresses host antiviral defence.
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