RIPK1 is required for ZBP1-driven necroptosis in human cells
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ICR Authors
Authors
Amusan, OT
Wang, S
Yin, C
Koehler, HS
Li, Y
Tenev, T
Wilson, R
Bellenie, B
Zhang, T
Wang, J
Liu, C
Seong, K
Poorbaghi, SL
Yates, J
Shen, Y
Upton, JW
Meier, P
Balachandran, S
Guo, H
Wang, S
Yin, C
Koehler, HS
Li, Y
Tenev, T
Wilson, R
Bellenie, B
Zhang, T
Wang, J
Liu, C
Seong, K
Poorbaghi, SL
Yates, J
Shen, Y
Upton, JW
Meier, P
Balachandran, S
Guo, H
Document Type
Journal Article
Date
2025-02-01
Date Accepted
2025-01-06
Abstract
<jats:p>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.</jats:p>
Citation
PLoS Biology, 2025, 23 (2),
Source Title
PLoS Biology
Publisher
PUBLIC LIBRARY SCIENCE
ISSN
1544-9173
eISSN
1545-7885
Collections
Research Team
Medicinal Chemistry 4
Cell Death and Immunity
Cell Death and Immunity