Linear Ubiquitin Assembly Complex Negatively Regulates RIG-I- and TRIM25-Mediated Type I Interferon Induction
Open accessAbstract
Upon detection of viral RNA, retinoic acid-inducible gene I (RIG-I) undergoes TRIM25-mediated K63-linked ubiquitination, leading to type I interferon (IFN) production. In this study, we demonstrate that the linear ubiquitin assembly complex (LUBAC), comprised of two RING-IBR-RING (RBR)-containing E3 ligases, HOIL-1L and HOIP, independently targets TRIM25 and RIG-I to effectively suppress virus-induced IFN production. RBR E3 ligase domains of HOIL-1L and HOIP bind and induce proteasomal degradation of TRIM25, whereas the NZF domain of HOIL-1L competes with TRIM25 for RIG-I binding. Consequently, both actions by the HOIL-1L/HOIP LUBAC potently inhibit RIG-I ubiquitination and antiviral activity, but in a mechanistically separate manner. Conversely, the genetic deletion or depletion of HOIL-1L and HOIP robustly enhances virus-induced type I IFN production. Taken together, the HOIL-1L/HOIP LUBAC specifically suppresses RIG-I ubiquitination and activation by inducing TRIM25 degradation and inhibiting TRIM25 interaction with RIG-I, resulting in the comprehensive suppression of the IFN-mediated antiviral signaling pathway.
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Several TRIM proteins regulate production and action of IFN-β during innate immune response.
“Several TRIM proteins regulate production and action of IFN-β during innate immune response.”
From TRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation (2015) · cites this paper as [35]
The Results section ('HOIL-1L/HOIP complex negatively regulates RIG-I-mediated type-I IFN induction'; page unavailable) shows that TRIM25 promotes RIG-I-mediated IFN-β promoter activation. The paper supports a role for TRIM25 in IFN-β production, but does not establish that several TRIM proteins regulate it or that they regulate IFN-β’s action. (LLM, conf=0.85)
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References 37 · Cited by 209
- Authors
- Inn, K.-S., Gack, M. U., Tokunaga, F., Shi, M., Wong, L.-Y., Iwai, K., & Jung, J. U.
- Affiliations
- University of Southern California (US)
- The University of Osaka (JP)
- Harvard University (US)
- Corresponding author
- Jung, Jae U.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2011-02
- Volume
- 41
- Issue
- 3
- Pages
- 354-365
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3070481
- OpenAlex
- W2106257653
- Cited by
- 209
- References
- 37
- Citations by year
- 2026: 2 · 2025: 12 · 2024: 14 · 2023: 10 · 2022: 10 · 2021: 15 · 2020: 18 · 2019: 12 · 2018: 13 · 2017: 14 · 2016: 18 · 2015: 17 · 2014: 14 · 2013: 13 · 2012: 14
- FWCI
- 7.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Research Foundation of Korea
- National Cancer Institute (CA082057, R01CA082057)
- National Institute of Allergy and Infectious Diseases (R01AI087846, R01AI073099, R01AI083355, U19AI083025, AI083355, AI087846-01A1, AI083025, R37AI087846)
- National Center for Research Resources (RR00 168, K26RR000168, P51RR000168)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- RIG-I, TRIM25, type I interferon, K63-linked ubiquitination, RBR E3 ubiquitin ligase, HOIL-1L, HOIP, proteasomal degradation, antiviral signaling, viral RNA sensing
- MeSH terms
- Tripartite Motif Proteins, Animals, Carrier Proteins, Cells, Cultured, Humans, Interferon Type I, Mutation, Transcription Factors, Signal Transduction, Receptors, Retinoic Acid, Ubiquitin-Protein Ligases, Mice, Ubiquitination
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