Histone deacetylase 4 promotes type I interferon signaling, restricts DNA viruses, and is degraded via vaccinia virus protein C6
| Autor: | Callum Talbot-Cooper, Yongxu Lu, Liane Dupont, Brian J. P. Huntly, Geoffrey L. Smith, Jennifer H. Stuart, Shuchi Agrawal-Singh, Joseph S. Snowden, Andrei I. Smid |
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| Přispěvatelé: | Lu, Yongxu [0000-0003-4701-5560], Smid, Andrei I [0000-0001-9732-0059], Snowden, Joseph S [0000-0001-7857-0634], Smith, Geoffrey L [0000-0002-3730-9955], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
STAT2 recruitment viruses Vaccinia virus Herpesvirus 1 Human Virus Replication medicine.disease_cause Microbiology Histone Deacetylases Virus Cell Line type I interferon signaling Viral Proteins 03 medical and health sciences 0302 clinical medicine Interferon Cell Line Tumor Vaccinia vaccinia virus protein C6 medicine Humans STAT2 immune evasion Histone deacetylase 5 Multidisciplinary biology Chemistry HDAC11 DNA Viruses histone deactylase 4 Biological Sciences HDAC4 HDAC1 3. Good health Cell biology Repressor Proteins HEK293 Cells 030104 developmental biology Herpes simplex virus PNAS Plus 030220 oncology & carcinogenesis Interferon Type I biology.protein HeLa Cells Signal Transduction medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance Histone deacetylases (HDACs) are regulators of host gene expression. HDAC4 is shown here to have an important role in type I interferon (IFN) signaling. Here, multiple cell lines lacking HDAC4 had impaired responses to IFN-α and were rescued by reintroduction of HDAC4. The biological significance of HDAC4 was demonstrated by the enhanced replication and spread of two DNA viruses, vaccinia virus (VACV) and herpes simplex virus type I, in HDAC4−/− cells, and their diminished replication when HDAC4 was overexpressed. Furthermore, HDAC4 was targeted for proteasomal degradation early after infection with VACV, and VACV protein C6, an inhibitor of type I IFN signaling, was necessary and sufficient for this degradation. In summary, HDAC4 is a restriction factor for large DNA viruses. Interferons (IFNs) represent an important host defense against viruses. Type I IFNs induce JAK-STAT signaling and expression of IFN-stimulated genes (ISGs), which mediate antiviral activity. Histone deacetylases (HDACs) perform multiple functions in regulating gene expression and some class I HDACs and the class IV HDAC, HDAC11, influence type I IFN signaling. Here, HDAC4, a class II HDAC, is shown to promote type I IFN signaling and coprecipitate with STAT2. Pharmacological inhibition of class II HDAC activity, or knockout of HDAC4 from HEK-293T and HeLa cells, caused a defective response to IFN-α. This defect in HDAC4−/− cells was rescued by reintroduction of HDAC4 or catalytically inactive HDAC4, but not HDAC1 or HDAC5. ChIP analysis showed HDAC4 was recruited to ISG promoters following IFN stimulation and was needed for binding of STAT2 to these promoters. The biological importance of HDAC4 as a virus restriction factor was illustrated by the observations that (i) the replication and spread of vaccinia virus (VACV) and herpes simplex virus type 1 (HSV-1) were enhanced in HDAC4−/− cells and inhibited by overexpression of HDAC4; and (ii) HDAC4 is targeted for proteasomal degradation during VACV infection by VACV protein C6, a multifunctional IFN antagonist that coprecipitates with HDAC4 and is necessary and sufficient for HDAC4 degradation. |
| Databáze: | OpenAIRE |
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