MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I interferon production after activation of the antiviral RIG-I-like receptors.

Abstract

BACKGROUND:

During a viral infection, the intracellular RIG-I-like receptors (RLRs) sense viral RNA and signal through the mitochondrial antiviral signaling adaptor MAVS (also known as IPS-1, Cardif and VISA) whose activation triggers a rapid production of type I interferons (IFN) and of pro-inflammatory cytokines through the transcription factors IRF3/IRF7 and NF-κB, respectively. While MAVS is essential for this signaling and known to operate through the scaffold protein NEMO and the protein kinase TBK1 that phosphorylates IRF3, its mechanism of action and regulation remain unclear.

RESULTS:

We report here that RLR activation triggers MAVS ubiquitination on lysine 7 and 10 by the E3 ubiquitin ligase TRIM25 and marks it for proteasomal degradation concomitantly with downstream signaling. Inhibition of this MAVS degradation with a proteasome inhibitor does not affect NF-κB signaling but it hampers IRF3 activation, and NEMO and TBK1, two essential mediators in type I IFN production, are retained at the mitochondria.

CONCLUSIONS:

These results suggest that MAVS functions as a recruitment platform that assembles a signaling complex involving NEMO and TBK1, and that the proteasome-mediated MAVS degradation is required to release the signaling complex into the cytosol, allowing IRF3 phosphorylation by TBK1.

• Authors: Céline Castanier, Naima Zemirli, Alain Portier, Dominique Garcin, Nicolas Bidère, Aimé Vazquez, Damien Arnoult
• Journal: BMC biology (BMC Biol) Vol. 10 Pg. 44 (May 24 2012) ISSN: 1741-7007 [Electronic] England
• PMID: 22626058 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• IKBKG protein, human
• Interferon Regulatory Factor-3
• Interferon Type I
• MAVS protein, human
• NF-kappa B
• Transcription Factors
• Tripartite Motif Proteins
• TRIM25 protein, human
• Ubiquitin-Protein Ligases
• Protein Serine-Threonine Kinases
• TBK1 protein, human
• I-kappa B Kinase
• Proteasome Endopeptidase Complex
• DEAD-box RNA Helicases

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• DEAD-box RNA Helicases (immunology, metabolism)
• HEK293 Cells
• HeLa Cells
• Humans
• I-kappa B Kinase (metabolism)
• Interferon Regulatory Factor-3 (metabolism)
• Interferon Type I (immunology)
• NF-kappa B (metabolism)
• Phosphorylation
• Proteasome Endopeptidase Complex (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Respirovirus Infections (immunology, metabolism)
• Sendai virus (immunology, metabolism)
• Signal Transduction
• Transcription Factors (metabolism)
• Tripartite Motif Proteins
• Ubiquitin-Protein Ligases (metabolism)
• Ubiquitination