RIPK1 is required for ZBP1-driven necroptosis in human cells
Necroptosis initiated by the host sensor Z-NA binding protein 1 (ZBP1) is essential for host defense against a growing number of viruses, including herpes simplex virus 1 (HSV-1). Studies with HSV-1 and other necroptogenic stimuli in murine settings have suggested that ZBP1 triggers necroptosis by directly complexing with the kinase RIPK3. Whether this is also the case in human cells, or whether additional co-factors are needed for ZBP1-mediated necroptosis, is unclear. Here, we show that ZBP1-induced necroptosis in human cells requires RIPK1. We have found that RIPK1 is essential for forming a stable and functional ZBP1-RIPK3 complex in human cells, but is dispensable for the formation of the equivalent murine complex. The receptor-interacting protein (RIP) homology interaction motif (RHIM) in RIPK3 is responsible for this difference between the 2 species, because replacing the RHIM in human RIPK3 with the RHIM from murine RIPK3 is sufficient to overcome the requirement for RIPK1 in human cells. These observations describe a critical mechanistic difference between mice and humans in how ZBP1 engages in necroptosis, with important implications for treating human diseases.
Authors
- Chaoran Yin (ORCID: https://orcid.org/0000-0002-4193-7022)
- Yixun Li (ORCID: https://orcid.org/0000-0003-2193-6126)
- Jason W. Upton (ORCID: https://orcid.org/0000-0002-4218-4026)
- Siddharth Balachandran (ORCID: https://orcid.org/0000-0003-2084-1803)
- Oluwamuyiwa T. Amusan
- Joseph Yates (ORCID: https://orcid.org/0000-0002-4236-2996)
- Pascal Meier (ORCID: https://orcid.org/0000-0003-2760-6523)
- Benjamin R. Bellenie (ORCID: https://orcid.org/0000-0001-9987-3079)
- Seyedeh Leila Poorbaghi
- Yuchen Shen
- Heather Koehler (ORCID: https://orcid.org/0000-0002-3061-9942)
- Tencho Tenev (ORCID: https://orcid.org/0000-0001-8762-1069)
- Chang Liu (ORCID: https://orcid.org/0000-0002-4335-4306)
- Jian Wang (ORCID: https://orcid.org/0000-0002-6545-3663)
- Shuqi Wang (ORCID: https://orcid.org/0000-0002-5764-8161)
- Ting Zhang (ORCID: https://orcid.org/0000-0001-9391-8926)
- Hongyan Guo (ORCID: https://orcid.org/0000-0002-6286-1741)
- Rebecca Wilson
- K. Wooi Seong
Institutions
- Fox Chase Cancer Center (US)
- Institute of Cancer Research (GB)
- Johns Hopkins University (US)
- Johns Hopkins Medicine (US)
- Breast Cancer Now (GB)
- Washington State University (US)
- Louisiana State University Health Sciences Center Shreveport (US)
- Auburn University (US)
Publication Details
- Journal
- PLoS Biology
- Published
- 2025-02-21
- DOI
- https://doi.org/10.1371/journal.pbio.3002845
- Citations
- 13
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 10.48
Funders
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- Division of Cancer Prevention, National Cancer Institute
- Cancer Research UK
- National Institute of General Medical Sciences