Abstract
We have isolated a novel interferon (IFN)-retinoid regulated cell death regulatory protein genes associated with retinoid-IFN-induced mortality (GRIM)-19 earlier. To understand its mechanism of action, we have employed a yeast-two-hybrid screen and identified serine protease HtrA2 as its binding partner. GRIM-19 physically interacts with HtrA2 and augments cell death in an IFN/all-trans retinoic acid (RA)-dependent manner. In the presence of GRIM-19, the HtrA2-driven destruction of the antiapoptotic protein X-linked inhibitor of apoptosis (XIAP) is augmented. These interactions were disrupted by an human herpes virus-8 (HHV-8)-coded oncoprotein, vIRF1, and conferred resistance to IFN/RA-induced cell death. These data show a critical role of HtrA2 in a cytokine-induced cell death response for the first time and its inhibition by a viral protein.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Apoptosis / drug effects
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Apoptosis / genetics
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Cell Line
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / genetics
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Cell Survival / physiology
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Drug Resistance
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Genetic Vectors / genetics
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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High-Temperature Requirement A Serine Peptidase 2
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Humans
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Interferon Regulatory Factors / genetics
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Interferon Regulatory Factors / metabolism
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Interferon-beta / pharmacology
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism*
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NADH, NADPH Oxidoreductases / genetics
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NADH, NADPH Oxidoreductases / metabolism*
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Protein Binding
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Serine Endopeptidases / genetics
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Serine Endopeptidases / metabolism*
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Transfection
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Tretinoin / pharmacology
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Two-Hybrid System Techniques
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Viral Proteins / genetics
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Viral Proteins / metabolism
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X-Linked Inhibitor of Apoptosis Protein / genetics
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X-Linked Inhibitor of Apoptosis Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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Interferon Regulatory Factors
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Mitochondrial Proteins
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Recombinant Fusion Proteins
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Viral Proteins
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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viral interferon regulatory factors
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Green Fluorescent Proteins
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Tretinoin
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Interferon-beta
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NADH, NADPH Oxidoreductases
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NDUFA13 protein, human
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Serine Endopeptidases
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HTRA2 protein, human
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High-Temperature Requirement A Serine Peptidase 2