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Loss of TRIM29 mitigates viral myocarditis by attenuating PERK-driven ER stress response in male mice

Author

Listed:
  • Junying Wang

    (Houston Methodist)

  • Wenting Lu

    (Houston Methodist)

  • Jerry Zhang

    (Houston Methodist)

  • Yong Du

    (Houston Methodist)

  • Mingli Fang

    (Houston Methodist)

  • Ao Zhang

    (Houston Methodist)

  • Gabriel Sungcad

    (Houston Methodist)

  • Samantha Chon

    (Houston Methodist)

  • Junji Xing

    (Houston Methodist
    Houston Methodist
    Weill Cornell Medicine, Cornell University)

Abstract

Viral myocarditis, an inflammatory disease of the myocardium, is a significant cause of sudden death in children and young adults. The current coronavirus disease 19 pandemic emphasizes the need to understand the pathogenesis mechanisms and potential treatment strategies for viral myocarditis. Here, we found that TRIM29 was highly induced by cardiotropic viruses and promoted protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated endoplasmic reticulum (ER) stress, apoptosis, and reactive oxygen species (ROS) responses that promote viral replication in cardiomyocytes in vitro. TRIM29 deficiency protected mice from viral myocarditis by promoting cardiac antiviral functions and reducing PERK-mediated inflammation and immunosuppressive monocytic myeloid-derived suppressor cells (mMDSC) in vivo. Mechanistically, TRIM29 interacted with PERK to promote SUMOylation of PERK to maintain its stability, thereby promoting PERK-mediated signaling pathways. Finally, we demonstrated that the PERK inhibitor GSK2656157 mitigated viral myocarditis by disrupting the TRIM29-PERK connection, thereby bolstering cardiac function, enhancing cardiac antiviral responses, and curbing inflammation and immunosuppressive mMDSC in vivo. Our findings offer insight into how cardiotropic viruses exploit TRIM29-regulated PERK signaling pathways to instigate viral myocarditis, suggesting that targeting the TRIM29-PERK axis could mitigate disease severity.

Suggested Citation

  • Junying Wang & Wenting Lu & Jerry Zhang & Yong Du & Mingli Fang & Ao Zhang & Gabriel Sungcad & Samantha Chon & Junji Xing, 2024. "Loss of TRIM29 mitigates viral myocarditis by attenuating PERK-driven ER stress response in male mice," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44745-x
    DOI: 10.1038/s41467-024-44745-x
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    References listed on IDEAS

    as
    1. Junji Xing & Ao Zhang & Yong Du & Mingli Fang & Laurie J. Minze & Yong-Jun Liu & Xian Chang Li & Zhiqiang Zhang, 2021. "Identification of poly(ADP-ribose) polymerase 9 (PARP9) as a noncanonical sensor for RNA virus in dendritic cells," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    2. Na Zhu & Wenling Wang & Zhidong Liu & Chaoyang Liang & Wen Wang & Fei Ye & Baoying Huang & Li Zhao & Huijuan Wang & Weimin Zhou & Yao Deng & Longfei Mao & Chongyu Su & Guangliang Qiang & Taijiao Jiang, 2020. "Morphogenesis and cytopathic effect of SARS-CoV-2 infection in human airway epithelial cells," Nature Communications, Nature, vol. 11(1), pages 1-8, December.
    3. Junji Xing & Ao Zhang & Hua Zhang & Jin Wang & Xian Chang Li & Mu-Sheng Zeng & Zhiqiang Zhang, 2017. "TRIM29 promotes DNA virus infections by inhibiting innate immune response," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
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