title: Inhibition of histone deacetylase activity suppresses IFN-γ induction of tripartite motif 22 via CHIP-mediated proteasomal degradation of IRF-1.
abstract: Tripartite motif (TRIM)22 plays an important role in IFN-mediated antiviral activity. We previously demonstrated that IFN regulatory factor (IRF)-1 was crucial for basal and IFN-induced TRIM22 transcription via binding to a novel cis-element named 5' extended IFN-stimulating response element. In this study, we investigated the role of histone deacetylase (HDAC) activity in TRIM22 induction by IFN-γ and its underlying mechanism. We found that the HDAC activity, especially that conferred by HDAC6, was required for IFN-γ-induced TRIM22 transcription. Importantly, inhibition of HDAC activity by trichostatin A (TSA) enhanced the hyperacetylation of heat shock protein (HSP)90 and suppressed its chaperone activity for IRF-1. Further study showed that TSA treatment promoted the proteasomal degradation of IRF-1 protein via enhancing the association of IRF-1 with the ubiquitin E3 ligase carboxyl terminus of Hsc70-interacting protein. Moreover, carboxyl terminus of Hsc70-interacting protein was found to be involved in the TSA-mediated inhibitory effect on IFN-γ induction of TRIM22 as well as other IRF-1-dependent IFN-stimulated genes. This study may provide novel insight into the role of HDAC activity in the transcriptional control of IFN-stimulated gene induction.
authors.affiliation: Department of Immunology, Institute for Immunobiology, Shanghai Medical College of Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Gao
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Shangshan
authors.initials: S
authors.lastname: Li
authors.forename: Qiao
authors.initials: Q
authors.lastname: Li
authors.forename: Sidong
authors.initials: S
authors.lastname: Xiong
mesh_terms: D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D006367:HeLa Cells; D056945:Hep G2 Cells; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000502:physiology; D015778:Minor Histocompatibility Antigens; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000070584:Tripartite Motif Proteins
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D050856:Interferon Regulatory Factor-1; D015778:Minor Histocompatibility Antigens; D012097:Repressor Proteins; C094314:TRIM22 protein, human; D000070584:Tripartite Motif Proteins; C012589:trichostatin A; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases