RIPK1 is required for ZBP1-driven necroptosis in human cells
Oluwamuyiwa T Amusan1, Shuqi Wang1, Chaoran Yin2
1Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America.
Plos Biology
|February 21, 2025
Summary
Host sensor Z-binding protein 1 (ZBP1) triggers necroptosis for viral defense. Human cells require RIPK1 for ZBP1-RIPK3 complex formation, unlike mice, revealing a key species-specific difference in necroptosis.
Area of Science:
- Immunology
- Cellular Biology
- Virology
Background:
- Necroptosis is a crucial host defense mechanism against viral infections.
- Z-binding protein 1 (ZBP1) initiates necroptosis, particularly against herpes simplex virus 1 (HSV-1).
- Previous studies in mice suggested ZBP1 directly complexes with RIPK3 to trigger necroptosis.
Purpose of the Study:
- To investigate the mechanism of ZBP1-mediated necroptosis in human cells.
- To determine if additional co-factors are required for ZBP1-induced necroptosis in humans.
- To elucidate species-specific differences in ZBP1-RIPK3 complex formation.
Main Methods:
- Comparative analysis of ZBP1-mediated necroptosis in human and murine cell lines.
- Investigating the role of RIPK1 in ZBP1-RIPK3 complex formation using biochemical assays.
- Utilizing genetic manipulation, including swapping receptor-interacting protein (RIP) homology interaction motifs (RHIMs) between human and murine RIPK3.
Main Results:
- ZBP1-induced necroptosis in human cells necessitates the involvement of RIPK1.
- RIPK1 is essential for a stable ZBP1-RIPK3 complex in human cells but not in murine cells.
- The RHIM domain of RIPK3 dictates this species-specific requirement, with murine RHIM enabling RIPK1-independent necroptosis in human cells.
Conclusions:
- A critical mechanistic divergence exists in ZBP1-mediated necroptosis between humans and mice.
- RIPK1 acts as a crucial co-factor for ZBP1-RIPK3 complex assembly in human cells.
- Understanding these species-specific differences has significant implications for developing targeted therapies for human diseases.
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