Abstract
Stringent regulation of the interferon (IFN) signalling pathway is essential for maintaining the immune response to pathogens and tumours. The transcription factor STAT1 is a crucial mediator of this response. Here, we show that hCAF1/CNOT7 regulates class I and II IFN pathways at different crucial steps. In resting cells, hCAF1 can control STAT1 trafficking by interacting with the latent form of STAT1 in the cytoplasm. IFN treatment induces STAT1 release, suggesting that hCAF1 may shield cytoplasmic STAT1 from undesirable stimulation. Consistently, hCAF1 silencing enhances STAT1 basal promoter occupancy associated with increased expression of a subset of STAT1-regulated genes. Consequently, hCAF1 knockdown cells exhibit an increased protection against viral infection and reduced viral replication. Furthermore, hCAF1 participates in the extinction of the IFN signal, through its deadenylase activity, by speeding up the degradation of some STAT1-regulated mRNAs. Since abnormal and unbalanced JAK/STAT activation is associated with immune disorders and cancer, hCAF1 could play a major role in innate immunity and oncogenesis, contributing to tumour escape.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Blotting, Western
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Proliferation / drug effects
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Chromatin Immunoprecipitation
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Cytoplasm / drug effects
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Cytoplasm / metabolism
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Exoribonucleases
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Female
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Fluorescent Antibody Technique
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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Humans
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Immunity, Innate
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Immunoprecipitation
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Interferons / pharmacology*
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MicroRNAs / genetics
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Oligonucleotide Array Sequence Analysis
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Phosphorylation
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Promoter Regions, Genetic / genetics
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Real-Time Polymerase Chain Reaction
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Repressor Proteins
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Reverse Transcriptase Polymerase Chain Reaction
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STAT1 Transcription Factor / antagonists & inhibitors*
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STAT1 Transcription Factor / genetics
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STAT1 Transcription Factor / metabolism
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Signal Transduction / drug effects*
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Virus Replication / drug effects*
Substances
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Biomarkers, Tumor
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CNOT8 protein, human
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MicroRNAs
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RNA, Messenger
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RNA, Small Interfering
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Repressor Proteins
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STAT1 Transcription Factor
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STAT1 protein, human
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Transcription Factors
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Interferons
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CNOT7 protein, human
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Exoribonucleases