Linear Ubiquitination of NEMO Negatively Regulates the Interferon Antiviral Response through Disruption of the MAVS-TRAF3 Complex

Belgnaoui, S. M. et al. 2012. Cell Host & Microbe. 12, 211-222

Speaker: Yi-Dan Ou (歐懿丹)                               Time: 15:10~16:00, Dec. 19, 2012

Commentator: Dr. Pin Ling (凌斌 博士)             Place: Room 601

Abstract:

The innate immune response is a first line of host defense against pathogens. Upon viral infection, viral nucleic acids are recognized by Toll-like receptors (TLRs) and cytosolic RIG-like receptors (RLRs). The cytosolic RLRs, including retinoic acid-inducible gene 1 (RIG-I) and Melanoma Differentiation-Associated protein (MDA) 5, bind to viral RNA and interact with downstream adaptor protein Mitochondrial antiviral-signaling protein (MAVS), which serves a signaling platform that triggers the interferon antiviral response via activation of the transcription factors nuclear factor (NF)-κB and interferon-regulating factor(IRF) 3. Recent studies have demonstrated that RIG-I/MDA5-mediated antiviral pathway is regulated by ubiquitination. Upon tumor necrosis factor-α stimulation, the E3 ligase linear ubiquitin assembly complex (LUBAC) mediates the formation of linearubiquitin chain on NF-κB essential modulator (NEMO), an crucial regulator of the IκB kinase complex, play an important role in regulation of NF-kB activation (1). Also, LUBAC-induced linear ubiquitination modulates the RIG-I-mediated antiviral pathway (2). Since NEMO is a known targetof LUBAC and impacts the regulation of NF-kB and IRF-3, the authors used chimeric forms of NEMO, modified by the addition of different linear ubiquitin moieties, to investigate whether IRF3 antiviral pathway is blocked via linear ubiquitination of NEMO. They demonstrated that linearubiquitinated NEMO competed with MAVS for tumor necross factor receptor associated factor (TRAF) 3 binding and inhibited IFN activation while stimulating NF-kB signaling. However, unmodified NEMO would not dissociate the MAVS-TRAF3 complex. Furthermore, in SHARPIN-deficient cpdm mouse embryonic fibroblasts, the replication of vesicular somatitis virus is decreased and IFN antiviral response is increased in the late stage of viral infection. NEMO therefore plays an important role in antiviral signaling. Linear ubiquitination of NEMO switches NEMO from a positive to a negative regulator of RIG-I antiviral signaling by disrupting the MAVS-TRAF3 complex and then terminates the IFN response at the late stage of viral infection.

References:

1.   Tokunaga, F. et al. 2009. Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol. 11, 123-132.

2.   Inn, K. S. et al. 2011. Inhibition of RIG-I-mediated signaling by Kaposi's sarcoma-associated herpesvirus-encoded deubiquitinase ORF64. J Virol. 85, 10899-10904.