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Linear ubiquitin assembly complex negatively regulates RIG-I- and TRIM25-mediated type I interferon induction
Kyung-Soo Inn1, Michaela U Gack, Fuminori Tokunaga
1Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, USA.
Molecular Cell
|February 5, 2011
Summary
The linear ubiquitin assembly complex (LUBAC) suppresses antiviral immunity by degrading TRIM25 and blocking RIG-I binding. This mechanism inhibits viral RNA detection and subsequent type I interferon production, crucial for innate immunity.
Area of Science:
- Immunology
- Molecular Biology
- Virology
Background:
- Retinoic acid-inducible gene I (RIG-I) initiates antiviral responses via type I interferon (IFN) production.
- TRIM25-mediated ubiquitination of RIG-I is essential for this IFN production pathway.
Purpose of the Study:
- To investigate the role of the linear ubiquitin assembly complex (LUBAC) in regulating RIG-I-mediated antiviral immunity.
- To elucidate the molecular mechanisms by which LUBAC, HOIL-1L, and HOIP modulate TRIM25 and RIG-I interactions.
Main Methods:
- Investigated the interaction between LUBAC components (HOIL-1L, HOIP) with TRIM25 and RIG-I.
- Assessed the impact of LUBAC on TRIM25 ubiquitination and proteasomal degradation.
- Analyzed the effect of LUBAC on RIG-I binding to TRIM25.
- Examined type I IFN production in cells with depleted or deleted LUBAC components.
Main Results:
- LUBAC, through HOIL-1L and HOIP, targets TRIM25 for proteasomal degradation via its RBR E3 ligase domains.
- HOIL-1L's NZF domain inhibits TRIM25 binding to RIG-I.
- These actions by LUBAC potently suppress RIG-I ubiquitination and antiviral activity through distinct mechanisms.
- Genetic deletion or depletion of HOIL-1L and HOIP significantly enhances virus-induced type I IFN production.
Conclusions:
- The HOIL-1L/HOIP LUBAC complex specifically suppresses RIG-I activation by inducing TRIM25 degradation and preventing TRIM25-RIG-I interaction.
- This LUBAC-mediated regulation comprehensively inhibits the RIG-I-dependent type I IFN antiviral signaling pathway.
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