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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing*
-
Amino Acid Sequence
-
Animals
-
Apoptosis Regulatory Proteins
-
Apoptosis*
-
Carrier Proteins / metabolism
-
Caspase 8
-
Caspase 9
-
Caspases*
-
Cell Line
-
Cell Transformation, Viral
-
Cysteine Endopeptidases / metabolism*
-
Fas-Associated Death Domain Protein
-
Gammaherpesvirinae / genetics
-
Gammaherpesvirinae / physiology*
-
Herpesvirus 2, Saimiriine / physiology
-
Humans
-
Membrane Glycoproteins / metabolism
-
Mice
-
Molecular Sequence Data
-
Receptors, Tumor Necrosis Factor / metabolism
-
Receptors, Tumor Necrosis Factor, Member 25
-
Sequence Homology, Amino Acid
-
Signal Transduction
-
TNF-Related Apoptosis-Inducing Ligand
-
Tumor Necrosis Factor-alpha / metabolism
-
Viral Proteins / physiology*
-
Virus Replication
-
fas Receptor / metabolism
Substances
-
Adaptor Proteins, Signal Transducing
-
Apoptosis Regulatory Proteins
-
Carrier Proteins
-
FADD protein, human
-
Fadd protein, mouse
-
Fas-Associated Death Domain Protein
-
Membrane Glycoproteins
-
Receptors, Tumor Necrosis Factor
-
Receptors, Tumor Necrosis Factor, Member 25
-
TNF-Related Apoptosis-Inducing Ligand
-
TNFRSF25 protein, human
-
TNFSF10 protein, human
-
Tnfrsf25 protein, mouse
-
Tnfsf10 protein, mouse
-
Tumor Necrosis Factor-alpha
-
Viral Proteins
-
fas Receptor
-
CASP8 protein, human
-
CASP9 protein, human
-
Casp8 protein, mouse
-
Casp9 protein, mouse
-
Caspase 8
-
Caspase 9
-
Caspases
-
Cysteine Endopeptidases