A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral
Francis Ka-Ming Chan1, Joanna Shisler, Jacqueline G Bixby
1Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. francis.chan@umassmed.edu
Abstract:
Members of the tumor necrosis factor (TNF) receptor (TNFR) superfamily are potent regulators of apoptosis, a process that is important for the maintenance of immune homeostasis. Recent evidence suggests that TNFR-1 and Fas and TRAIL receptors can also trigger an alternative form of cell death that is morphologically distinct from apoptosis. Because distinct molecular components including the serine/threonine protein kinase receptor-interacting protein (RIP) are required, we have referred to this alternative form of cell death as "programmed necrosis." We show that TNFR-2 signaling can potentiate programmed necrosis via TNFR-1. When cells were pre-stimulated through TNFR-2 prior to subsequent activation of TNFR-1, enhanced cell death and recruitment of RIP to the TNFR-1 complex were observed. However, TNF-induced programmed necrosis was normally inhibited by caspase-8 cleavage of RIP. To ascertain the physiological significance of RIP and programmed necrosis, we infected Jurkat cells with vaccinia virus (VV) and found that VV-infected cells underwent programmed necrosis in response to TNF, but deficiency of RIP rescued the infected cells from TNF-induced cytotoxicity. Moreover, TNFR-2-/- mice exhibited reduced inflammation in the liver and defective viral clearance during VV infection. Interestingly, death effector domain-containing proteins such as MC159, E8, K13, and cellular FLIP, but not the apoptosis inhibitors Bcl-xL, p35, and XIAP, potently suppressed programmed necrosis. Thus, TNF-induced programmed necrosis is facilitated by TNFR-2 signaling and caspase inhibition and may play a role in controlling viral infection.
Insights
Tumor necrosis factor receptor-2 (TNFR-2) signaling enhances programmed necrosis via TNFR-1, a distinct cell death pathway. This process, regulated by receptor-interacting protein (RIP) and caspase inhibition, plays a role in viral infection control.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Tumor necrosis factor receptor (TNFR) superfamily members regulate immune homeostasis through apoptosis.
- Alternative cell death pathways distinct from apoptosis are triggered by TNFR-1, Fas, and TRAIL receptors.
- Programmed necrosis, a distinct cell death form, requires specific components like receptor-interacting protein (RIP).
Purpose of the Study:
- To investigate the role of TNFR-2 signaling in programmed necrosis.
- To elucidate the involvement of RIP and caspase inhibition in TNF-induced programmed necrosis.
- To determine the physiological significance of programmed necrosis in viral infections.
Main Methods:
- Cells were pre-stimulated via TNFR-2 before TNFR-1 activation to assess programmed necrosis.
- Receptor-interacting protein (RIP) recruitment to the TNFR-1 complex was analyzed.
- Vaccinia virus (VV) infection models in Jurkat cells and TNFR-2 knockout mice were used to study viral control and inflammation.
Main Results:
- TNFR-2 signaling potentiated TNFR-1-mediated programmed necrosis, enhancing cell death and RIP recruitment.
- Caspase-8 cleavage of RIP normally inhibited TNF-induced programmed necrosis.
- VV-infected cells underwent programmed necrosis; RIP deficiency rescued cells from TNF-induced cytotoxicity.
- TNFR-2 knockout mice showed reduced liver inflammation and impaired viral clearance during VV infection.
- Specific death effector domain proteins, but not general apoptosis inhibitors, suppressed programmed necrosis.
Conclusions:
- TNF-induced programmed necrosis is facilitated by TNFR-2 signaling and caspase inhibition.
- RIP is crucial for TNF-induced programmed necrosis, particularly in viral infections.
- Programmed necrosis may serve as a host defense mechanism against viral infections.
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