Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. Signal., 3 November 2009
Vol. 2, Issue 95, p. ec354
[DOI: 10.1126/scisignal.295ec354]


Immunology IRF-3 and Ubiquitin

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

One mechanism by which cells detect the presence of cytosolic viruses is through retinoic acid–inducible gene I (RIG-I), which binds to viral RNA and associates with the mitochondrial outer membrane adaptor protein MAVS. MAVS activates the transcription factors nuclear factor {kappa}B (NF-{kappa}B) and interferon regulatory factor 3 (IRF-3), which induce production of the type I interferons required for the antiviral response. However, the mechanism by which MAVS activates IRF-3 is incompletely understood. Noting that ubiquitination is thought to regulate the RIG-I pathway, Zeng et al. devised a cell-free system in which mitochondria isolated from uninfected or infected HEK 293T cells were incubated with cytosolic extracts from uninfected cells. Phosphorylated and dimerized (and therefore activated) IRF-3 was detected in cytosolic extracts incubated with mitochondria from infected HEK 293T cells. Purification of factors responsible for IRF-3 activation from cytosolic fractions led to the identification of the E2 ubiquitin-conjugating enzyme Ubc5. Experiments in cells treated with specific short hairpin RNAs (shRNAs) showed that catalytically active Ubc5 was required for RIG-I- and MAVS-dependent activation of IRF-3. Tests of a panel of ubiquitin mutants showed that Lys63-mediated, but not Lys48-mediated, polyubiquitination was required for the activation of IRF-3; however, the E3 ubiquitin ligase involved was not identified. Consistent with a study that implicated inhibitor of NF-{kappa}B kinase {gamma} (IKK{gamma}, also known as NEMO) in the RIG-I to IRF-3 pathway, experiments in the cell-free system showed that two ubiquitin-binding domains of NEMO were required for the activation of IRF-3. Together, these data suggest that Lys63-mediated polyubiquitination is required to activate IRF-3 as part of the antiviral immune response.

W. Zeng, M. Xu, S. Liu, L. Sun, Z. J. Chen, Key role of Ubc5 and Lysine-63 polyubiquitination in viral activation of IRF3. Mol. Cell 36, 315–325 (2009). [PubMed]

Citation: J. F. Foley, IRF-3 and Ubiquitin. Sci. Signal. 2, ec354 (2009).

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882