RIPK1 is essential for Herpes Simplex Virus-triggered ZBP1-dependent necroptosis in human cells
Oluwamuyiwa T Amusan1, Shuqi Wang1, Chaoran Yin2
1Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71130, USA.
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 RIP Homology Interaction Motif (RHIM) in RIPK3 is responsible for this difference between the two 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 defense protein Z-Nucleic Acid Binding Protein-1 (ZBP1) triggers necroptosis. Human cells require RIPK1 for ZBP1-RIPK3 complex formation, unlike mice, highlighting a key species-specific difference in viral defense mechanisms.
Area of Science:
- Immunology
- Cellular Biology
- Virology
Background:
- Necroptosis, a programmed cell death pathway, is crucial for host defense against viral infections like Herpes Simplex Virus-1 (HSV-1).
- The host sensor Z-Nucleic Acid Binding Protein-1 (ZBP1) initiates necroptosis, and in mice, it's thought to directly complex with RIPK3 kinase.
- The precise mechanism of ZBP1-mediated necroptosis in human cells, and the potential involvement of co-factors, remains largely uncharacterized.
Purpose of the Study:
- To elucidate the mechanism of ZBP1-induced necroptosis in human cells.
- To identify species-specific differences in ZBP1 complex formation between human and murine cells.
- To investigate the role of RIPK1 and RIPK3 in ZBP1-mediated necroptosis.
Main Methods:
- Utilized human and murine cell lines.
- Investigated protein-protein interactions using co-immunoprecipitation assays.
- Employed genetic manipulation, including RIPK3 RHIM domain swapping between human and murine sequences.
Main Results:
- ZBP1-induced necroptosis in human cells necessitates the presence of RIPK1.
- RIPK1 is essential for the formation of a stable ZBP1-RIPK3 complex in human cells.
- RIPK1 is dispensable for the ZBP1-RIPK3 complex formation in murine cells.
- The RIP Homology Interaction Motif (RHIM) of RIPK3 dictates this species-specific requirement for RIPK1.
Conclusions:
- A critical mechanistic divergence exists in ZBP1-mediated necroptosis between human and murine cells.
- RIPK1 acts as a crucial co-factor for ZBP1-RIPK3 complex assembly in humans, but not in mice.
- The RHIM domain of RIPK3 underlies this species-specific difference, with implications for human disease therapies.
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