DAI Another Way: Necroptotic Control of Viral Infection
Jason W Upton1, William J Kaiser2
1Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.
Cell Host & Microbe
|March 11, 2017
Abstract:
Interrogation of murine cytomegalovirus (MCMV)-encoded cell-death suppressors revealed that necroptosis functions as a trap door to eliminate virally infected cells. This crucial host defense pathway is orchestrated by the sensing of infection by DAI/ZBP-1, engagement of the kinase RIPK3, and subsequent membrane permeablization by the pseudokinase MLKL.
Insights
Murine cytomegalovirus (MCMV) uses cell-death suppressors, but necroptosis acts as a defense. This pathway eliminates infected cells via DAI/ZBP-1, RIPK3, and MLKL.
Area of Science:
- Virology
- Immunology
- Cell Biology
Background:
- Murine cytomegalovirus (MCMV) encodes proteins to counteract host defenses.
- Cell death pathways are critical for controlling viral infections.
- Necroptosis is a regulated form of necrosis with potential antiviral roles.
Purpose of the Study:
- To investigate the role of MCMV-encoded cell-death suppressors.
- To elucidate the function of necroptosis in MCMV infection.
- To identify the key molecular players in MCMV-induced necroptosis.
Main Methods:
- Interrogation of MCMV mutants lacking cell-death suppressors.
- Analysis of host cell-death pathways during MCMV infection.
- Molecular assays to detect key necroptosis mediators (DAI/ZBP-1, RIPK3, MLKL).
Main Results:
- Necroptosis functions as a critical host defense mechanism against MCMV.
- The host sensor DAI/ZBP-1 initiates the necroptosis pathway upon MCMV infection.
- Activation of RIPK3 kinase and MLKL pseudokinase leads to membrane permeabilization and cell elimination.
Conclusions:
- Necroptosis acts as a 'trap door' to eliminate MCMV-infected cells.
- DAI/ZBP-1, RIPK3, and MLKL are essential components of this antiviral necroptosis pathway.
- Understanding this pathway offers insights into host-virus conflict and potential therapeutic strategies.
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