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.
Abstract:
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.
Insights
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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