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Linear ubiquitination of NEMO negatively regulates the interferon antiviral response through disruption of the

S Mehdi Belgnaoui1, Suzanne Paz, Sara Samuel

  • 1Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada.

Cell Host & Microbe
|August 21, 2012
PubMed

Insights

The linear ubiquitin assembly complex (LUBAC) regulates antiviral immunity by modifying NEMO. This modification inhibits RIG-I-mediated interferon production while promoting NF-κB signaling, ultimately dampening the host

Area of Science:

  • Innate immunity
  • RNA sensing pathways
  • Ubiquitination signaling

Background:

  • Retinoic acid-inducible protein I (RIG-I) and Melanoma differentiation-associated protein 5 (Mda5) are key sensors of intracellular viral RNA.
  • These sensors initiate antiviral responses through the MAVS adaptor protein, leading to interferon (IFN) and cytokine production via IRF and NF-κB pathways.
  • NEMO is a crucial adaptor protein required for both IRF and NF-κB pathway activation in antiviral signaling.

Purpose of the Study:

  • To investigate the role of the linear ubiquitin assembly complex (LUBAC) in regulating the RIG-I signaling pathway.
  • To elucidate how LUBAC affects virus-mediated interferon induction and NF-κB activation.
  • To understand the mechanism by which LUBAC modulates NEMO function in innate immune signaling.

Main Methods:

  • Investigated the interaction between LUBAC components (HOIL-1L, HOIP, SHARPIN) and the RIG-I signaling pathway.
  • Analyzed the effect of LUBAC on NEMO ubiquitination status, specifically linear ubiquitination.
  • Examined the impact of linear ubiquitinated NEMO on MAVS-TRAF3 complex formation and downstream signaling.
  • Assessed viral replication and IFN production in SHARPIN-deficient mouse embryonic fibroblasts (MEFs).

Main Results:

  • LUBAC was found to downregulate virus-mediated IFN induction by targeting NEMO for linear ubiquitination.
  • Linear ubiquitination of NEMO led to its association with TRAF3, disrupting the MAVS-TRAF3 complex and inhibiting IFN activation.
  • This process simultaneously enhanced NF-κB-dependent signaling.
  • SHARPIN deficiency resulted in increased IFN production and decreased vesicular stomatitis virus replication in MEFs.

Conclusions:

  • LUBAC acts as a negative regulator of RIG-I-mediated type I IFN responses through linear ubiquitination of NEMO.
  • Linear ubiquitination switches NEMO's function from a positive to a negative regulator in the RIG-I pathway, attenuating IFN production.
  • This regulatory mechanism highlights a critical interplay between ubiquitination and innate immune signaling in controlling viral infections.

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