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TRIM29 promotes DNA virus infections by inhibiting innate immune response
Junji Xing1, Ao Zhang2, Hua Zhang2
1Immunobiology and Transplant Science Center, Houston Methodist Research Institute, Houston, TX, 77030, USA.
Abstract:
Many double-stranded DNA viruses, such as Epstein-Barr virus, can establish persistent infection, but the underlying virus-host interactions remain poorly understood. Here we report that in human airway epithelial cells Epstein-Barr virus induces TRIM29, a member of the TRIM family of proteins, to inhibit innate immune activation. Knockdown of TRIM29 in airway epithelial cells enhances type I interferon production, and in human nasopharyngeal carcinoma cells results in almost complete Epstein-Barr virus clearance. TRIM29 is also highly induced by cytosolic double-stranded DNA in myeloid dendritic cells. TRIM29 -/- mice have lower adenovirus titers in the lung, and are resistant to lethal herpes simplex virus-1 infection due to enhanced production of type I interferon. Mechanistically, TRIM29 induces K48-linked ubiquitination of Stimulator of interferon genes, a key adaptor in double-stranded DNA-sensing pathway, followed by its rapid degradation. These data demonstrate that Epstein-Barr virus and possible other double-stranded DNA viruses use TRIM29 to suppress local innate immunity, leading to the persistence of DNA virus infections.Proteins of the TRIM family have regulatory functions in immune signaling, often via ubiquitination of target proteins. Here, the authors show that TRIM29 is induced upon infection with DNA viruses, resulting in degradation of STING, decreased interferon signaling and increased pathogenicity in mice.
Insights
Epstein-Barr virus and other DNA viruses use TRIM29 to suppress the immune system. This protein targets STING for degradation, hindering innate immunity and promoting persistent viral infections.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Double-stranded DNA viruses can cause persistent infections through poorly understood virus-host interactions.
- The TRIM (Tripartite Motif) protein family plays a role in regulating immune signaling, often through ubiquitination.
Purpose of the Study:
- To investigate the role of TRIM29 in Epstein-Barr virus (EBV) infection and innate immune response.
- To elucidate the mechanism by which TRIM29 influences DNA virus persistence.
Main Methods:
- Studied TRIM29 induction in human airway epithelial cells and myeloid dendritic cells upon viral infection.
- Utilized TRIM29 knockdown in cell lines and TRIM29 knockout mice to assess its impact on viral load and immune response.
- Investigated the molecular mechanism involving ubiquitination and degradation of STING (Stimulator of Interferon Genes).
Main Results:
- Epstein-Barr virus infection induces TRIM29 in human airway epithelial cells, inhibiting innate immune activation.
- TRIM29 knockdown enhanced type I interferon production and led to EBV clearance in nasopharyngeal carcinoma cells.
- TRIM29 knockout mice exhibited reduced adenovirus titers and resistance to herpes simplex virus-1 infection due to increased type I interferon.
- TRIM29 targets STING for K48-linked ubiquitination and degradation, dampening the DNA-sensing pathway.
Conclusions:
- Epstein-Barr virus and potentially other double-stranded DNA viruses exploit TRIM29 to evade local innate immunity, facilitating persistent infections.
- TRIM29-mediated degradation of STING is a key mechanism for viral immune evasion and increased pathogenicity.