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

Junying Wang, Wenting Lu, Jerry Zhang, Yong Du, Mingli Fang, Ao Zhang, Gabriel Sungcad, Samantha Chon, Junji Xing

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number3481
Pages (from-to)3481
JournalNature Communications
Volume15
Issue number1
DOIs
StatePublished - Apr 25 2024

Keywords

  • Animals
  • Humans
  • Male
  • Mice
  • Adenine/analogs & derivatives
  • Apoptosis
  • eIF-2 Kinase/metabolism
  • Endoplasmic Reticulum Stress
  • Indoles
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocarditis/virology
  • Myocardium/pathology
  • Myocytes, Cardiac/metabolism
  • Reactive Oxygen Species/metabolism
  • Signal Transduction
  • Transcription Factors/metabolism
  • Virus Replication

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint

Dive into the research topics of 'Loss of TRIM29 mitigates viral myocarditis by attenuating PERK-driven ER stress response in male mice'. Together they form a unique fingerprint.

Cite this