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Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors
M Thome1, P Schneider, K Hofmann
1Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Abstract:
Viruses have evolved many distinct strategies to avoid the host's apoptotic response. Here we describe a new family of viral inhibitors (v-FLIPs) which interfere with apoptosis signalled through death receptors and which are present in several gamma-herpesviruses (including Kaposi's-sarcoma-associated human herpesvirus-8), as well as in the tumorigenic human molluscipoxvirus. v-FLIPs contain two death-effector domains which interact with the adaptor protein FADD, and this inhibits the recruitment and activation of the protease FLICE by the CD95 death receptor. Cells expressing v-FLIPs are protected against apoptosis induced by CD95 or by the related death receptors TRAMP and TRAIL-R. The herpesvirus saimiri FLIP is detected late during the lytic viral replication cycle, at a time when host cells are partially protected from CD95-ligand-mediated apoptosis. Protection of virus-infected cells against death-receptor-induced apoptosis may lead to higher virus production and contribute to the persistence and oncogenicity of several FLIP-encoding viruses.
Insights
Viruses use viral FLIPs (v-FLIPs) to block host cell death pathways, promoting viral replication. These inhibitors protect infected cells from apoptosis, aiding viral persistence and cancer development.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- Viruses employ diverse mechanisms to evade host cell apoptosis.
- Apoptosis is a crucial host defense mechanism against viral infections.
Purpose of the Study:
- To identify and characterize a new family of viral inhibitors, viral FLIPs (v-FLIPs).
- To investigate the role of v-FLIPs in viral evasion of apoptosis and their impact on viral pathogenesis.
Main Methods:
- Described v-FLIPs from gamma-herpesviruses and molluscipoxvirus.
- Investigated v-FLIP interaction with FADD and inhibition of FLICE recruitment by CD95.
- Assessed cell protection against CD95, TRAMP, and TRAIL-R-mediated apoptosis in v-FLIP-expressing cells.
Main Results:
- Identified v-FLIPs containing death-effector domains that bind FADD.
- Demonstrated v-FLIPs inhibit CD95-mediated apoptosis by blocking FLICE activation.
- Showed v-FLIPs protect cells from apoptosis induced by multiple death receptors.
- Observed v-FLIP expression late in viral replication, coinciding with host cell protection.
Conclusions:
- v-FLIPs are a novel class of viral apoptosis inhibitors.
- v-FLIPs contribute to viral persistence and oncogenicity by protecting infected cells from death receptor-mediated apoptosis.
- Targeting v-FLIPs could offer therapeutic strategies against viral infections and associated cancers.