Gamma interferon triggers interaction between ICSBP (IRF-8) and TEL, recruiting the histone deacetylase HDAC3 to the interferon-responsive element.
ICSBP (IRF-8) is a transcription factor of the IRF family expressed only in the immune system. It is induced in macrophages by gamma interferon (IFN-gamma) and contributes to macrophage functions. By interacting with Ets family protein PU.1, ICSBP binds to the IRF/Ets composite element and stimulates transcription. ICSBP binds to another DNA element, the IFN-stimulated response element (ISRE), a common target of the IRF family. Limited knowledge as to how ICSBP and other IRF proteins regulate ISRE-dependent transcription in IFN-gamma-activated macrophages is available. By mass-spectrometric analysis of ISRE-bound proteins in macrophages, we identified TEL, another Ets member, as a factor recruited to the element in an IFN-gamma-dependent manner. In vitro analysis with recombinant proteins indicated that this recruitment is due to a direct interaction between ICSBP and TEL, which is enhanced by the presence of ISRE. Significantly, the interaction with TEL in turn resulted in the recruitment of the histone deacetytase HDAC3 to the ISRE, causing increased repression of IFN-gamma-mediated reporter activity through the ISRE. This repression may provide a negative-feedback mechanism operating after the initial transcriptional activation by IFN-gamma. By associating with two different Ets family proteins, ICSBP exerts a dual function in IFN-gamma-dependent gene regulation in an immune system-specific manner.
Kuwata
Takeshi
T
Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Gongora
Celine
C
Kanno
Yuka
Y
Sakaguchi
Kazuyasu
K
Tamura
Tomohiko
T
Kanno
Tomohiko
T
Basrur
Venkatesha
V
Martinez
Robert
R
Appella
Ettore
E
Golub
Todd
T
Ozato
Keiko
K
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma / Q000378:metabolism* / Q000502:physiology; D007372:Interferons / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097764:ETS Translocation Variant 6 Protein; D000099185:Interferon Regulatory Factor-8; D000099186:Histone Deacetylase 3
D004247:DNA; D004268:DNA-Binding Proteins; D005982:Glutathione Transferase; D006655:Histone Deacetylases; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D007372:Interferons; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; D000099185:Interferon Regulatory Factor-8; D000099186:Histone Deacetylase 3