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Updated: Jul 10, 2025
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Published on: January 26, 2019
LUBAC is required for RIG-I sensing of RNA viruses
Helena C Teague1, Charlotte Lefevre1, Eva Rieser2,3
1Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, UK.
Abstract:
The ability of cells to mount an interferon response to virus infections depends on intracellular nucleic acid sensing pattern recognition receptors (PRRs). RIG-I is an intracellular PRR that binds short double-stranded viral RNAs to trigger MAVS-dependent signalling. The RIG-I/MAVS signalling complex requires the coordinated activity of multiple kinases and E3 ubiquitin ligases to activate the transcription factors that drive type I and type III interferon production from infected cells. The linear ubiquitin chain assembly complex (LUBAC) regulates the activity of multiple receptor signalling pathways in both ligase-dependent and -independent ways. Here, we show that the three proteins that constitute LUBAC have separate functions in regulating RIG-I signalling. Both HOIP, the E3 ligase capable of generating M1-ubiquitin chains, and LUBAC accessory protein HOIL-1 are required for viral RNA sensing by RIG-I. The third LUBAC component, SHARPIN, is not required for RIG-I signalling. These data cement the role of LUBAC as a positive regulator of RIG-I signalling and as an important component of antiviral innate immune responses.
Insights
The linear ubiquitin chain assembly complex (LUBAC) regulates cellular antiviral responses. HOIP and HOIL-1 within LUBAC are crucial for RIG-I sensing of viral RNA, enhancing innate immunity.
Area of Science:
- Immunology
- Molecular Biology
- Virology
Background:
- Cellular antiviral defense relies on intracellular pattern recognition receptors (PRRs) sensing viral nucleic acids.
- RIG-I (Retinoic acid-inducible gene I) is a key PRR that detects viral double-stranded RNA and initiates MAVS-dependent signaling.
- The RIG-I/MAVS pathway activation involves kinases and E3 ubiquitin ligases to induce interferon production.
Purpose of the Study:
- To elucidate the specific roles of the three protein components of the linear ubiquitin chain assembly complex (LUBAC) in regulating RIG-I signaling.
- To determine the necessity of HOIP, HOIL-1, and SHARPIN for effective viral RNA sensing and subsequent interferon response.
Main Methods:
- Investigated the function of LUBAC components in RIG-I signaling pathways.
- Assessed the requirement of HOIP, HOIL-1, and SHARPIN for viral RNA sensing by RIG-I.
- Analyzed the impact of LUBAC components on MAVS-dependent signaling and interferon production.
Main Results:
- The E3 ligase HOIP (HECT, RLD, and Phox2 domain-containing protein) and the accessory protein HOIL-1 (also known as RBCK1) are essential for RIG-I-mediated sensing of viral RNA.
- SHARPIN, the third component of LUBAC, is dispensable for RIG-I signaling.
- LUBAC acts as a positive regulator in the RIG-I signaling pathway.
Conclusions:
- LUBAC, through its components HOIP and HOIL-1, plays a critical role in initiating antiviral innate immune responses via RIG-I activation.
- These findings highlight the distinct functional contributions of LUBAC subunits in antiviral immunity.
- LUBAC is confirmed as a vital regulator of RIG-I signaling and a key player in cellular defense against viral infections.
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