Recent advances in ZBP1-derived PANoptosis against viral infections

Front Immunol. 2023 May 16:14:1148727. doi: 10.3389/fimmu.2023.1148727. eCollection 2023.


Innate immunity is an important first line of defense against pathogens, including viruses. These pathogen- and damage-associated molecular patterns (PAMPs and DAMPs, respectively), resulting in the induction of inflammatory cell death, are detected by specific innate immune sensors. Recently, Z-DNA binding protein 1 (ZBP1), also called the DNA-dependent activator of IFN regulatory factor (DAI) or DLM1, is reported to regulate inflammatory cell death as a central mediator during viral infection. ZBP1 is an interferon (IFN)-inducible gene that contains two Z-form nucleic acid-binding domains (Zα1 and Zα2) in the N-terminus and two receptor-interacting protein homotypic interaction motifs (RHIM1 and RHIM2) in the middle, which interact with other proteins with the RHIM domain. By sensing the entry of viral RNA, ZBP1 induces PANoptosis, which protects host cells against viral infections, such as influenza A virus (IAV) and herpes simplex virus (HSV1). However, some viruses, particularly coronaviruses (CoVs), induce PANoptosis to hyperactivate the immune system, leading to cytokine storm, organ failure, tissue damage, and even death. In this review, we discuss the molecular mechanism of ZBP1-derived PANoptosis and pro-inflammatory cytokines that influence the double-edged sword of results in the host cell. Understanding the ZBP1-derived PANoptosis mechanism may be critical for improving therapeutic strategies.

Keywords: PANoptosis; ZBP1; apoptosis; inflammasome; interferon; necroptosis; pyroptosis; virus.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Death
  • Cytokines / metabolism
  • Humans
  • Immunity, Innate
  • RNA-Binding Proteins* / metabolism
  • Virus Diseases*


  • RNA-Binding Proteins
  • Cytokines

Grants and funding

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2022R1C1C1007544 to SL), by grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare (HV22C015600 to SL), by research grant from the Korea National Institute of Health funded by Korea Disease Control and Prevention Agency (KDCA) (2.221151.01 to SL), by research grant from Korea Virus Research Institute (KVRI), Institute for Basic Science (IBS) (2.230625.01 to SL), by research fund from Ulsan National Institute of Science & Technology (UNIST) (1.220112.01, 1.220107.01 to SL). This study also received funding from Yuhan Corporation (2.220961.01 to SL). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.