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TRIM18 is a critical regulator of viral myocarditis and organ inflammation.
Fang, Mingli; Zhang, Ao; Du, Yong; Lu, Wenting; Wang, Junying; Minze, Laurie J; Cox, Timothy C; Li, Xian Chang; Xing, Junji; Zhang, Zhiqiang.
  • Fang M; Department of Surgery and Immunobiology and Transplant Science Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, 77030, USA.
  • Zhang A; Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China.
  • Du Y; Department of Surgery and Immunobiology and Transplant Science Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, 77030, USA.
  • Lu W; Department of Laboratory Medicine, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.
  • Wang J; Department of Surgery and Immunobiology and Transplant Science Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, 77030, USA.
  • Minze LJ; Department of Surgery and Immunobiology and Transplant Science Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, 77030, USA.
  • Cox TC; Department of Surgery and Immunobiology and Transplant Science Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, 77030, USA.
  • Li XC; Department of Surgery and Immunobiology and Transplant Science Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, 77030, USA.
  • Xing J; Department of Oral & Craniofacial Sciences, School of Dentistry & Department of Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, 64108, USA.
  • Zhang Z; Department of Surgery and Immunobiology and Transplant Science Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, 77030, USA.
J Biomed Sci ; 29(1): 55, 2022 Jul 31.
Article in English | MEDLINE | ID: covidwho-1965824
ABSTRACT

BACKGROUND:

Infections by viruses including severe acute respiratory syndrome coronavirus 2 could cause organ inflammations such as myocarditis, pneumonia and encephalitis. Innate immunity to viral nucleic acids mediates antiviral immunity as well as inflammatory organ injury. However, the innate immune mechanisms that control viral induced organ inflammations are unclear.

METHODS:

To understand the role of the E3 ligase TRIM18 in controlling viral myocarditis and organ inflammation, wild-type and Trim18 knockout mice were infected with coxsackievirus B3 for inducing viral myocarditis, influenza A virus PR8 strain and human adenovirus for inducing viral pneumonia, and herpes simplex virus type I for inducing herpes simplex encephalitis. Mice survivals were monitored, and heart, lung and brain were harvested for histology and immunohistochemistry analysis. Real-time PCR, co-immunoprecipitation, immunoblot, enzyme-linked immunosorbent assay, luciferase assay, flow cytometry, over-expression and knockdown techniques were used to understand the molecular mechanisms of TRIM18 in regulating type I interferon (IFN) production after virus infection in this study.

RESULTS:

We find that knockdown or deletion of TRIM18 in human or mouse macrophages enhances production of type I IFN in response to double strand (ds) RNA and dsDNA or RNA and DNA virus infection. Importantly, deletion of TRIM18 protects mice from viral myocarditis, viral pneumonia, and herpes simplex encephalitis due to enhanced type I IFN production in vivo. Mechanistically, we show that TRIM18 recruits protein phosphatase 1A (PPM1A) to dephosphorylate TANK binding kinase 1 (TBK1), which inactivates TBK1 to block TBK1 from interacting with its upstream adaptors, mitochondrial antiviral signaling (MAVS) and stimulator of interferon genes (STING), thereby dampening antiviral signaling during viral infections. Moreover, TRIM18 stabilizes PPM1A by inducing K63-linked ubiquitination of PPM1A.

CONCLUSIONS:

Our results indicate that TRIM18 serves as a negative regulator of viral myocarditis, lung inflammation and brain damage by downregulating innate immune activation induced by both RNA and DNA viruses. Our data reveal that TRIM18 is a critical regulator of innate immunity in viral induced diseases, thereby identifying a potential therapeutic target for treatment.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Virus Diseases / Encephalitis, Herpes Simplex / Ubiquitin-Protein Ligases / Myocarditis Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: J Biomed Sci Journal subject: Medicine Year: 2022 Document Type: Article Affiliation country: S12929-022-00840-z

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Virus Diseases / Encephalitis, Herpes Simplex / Ubiquitin-Protein Ligases / Myocarditis Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: J Biomed Sci Journal subject: Medicine Year: 2022 Document Type: Article Affiliation country: S12929-022-00840-z