Regulation of tumor necrosis factor alpha gene expression by mycobacteria involves the assembly of a unique enhanceosome dependent on the coactivator proteins CBP/p300.
Tumor necrosis factor alpha (TNF-alpha) plays an important role in host containment of infection by Mycobacterium tuberculosis, one of the leading causes of death by an infectious agent globally. Using the pathogenic M. tuberculosis strain H37Rv, we present evidence that upon stimulation of monocytic cells by M. tuberculosis a unique TNF-alpha enhanceosome is formed, and it is distinct from the TNF-alpha enhanceosome that forms in T cells stimulated by antigen engagement or virus infection. A distinct set of activators including ATF-2, c-jun, Ets, Sp1, Egr-1 and the coactivator proteins CBP/p300 are recruited to the TNF-alpha promoter after stimulation with M. tuberculosis. Furthermore, the formation of this enhanceosome is dependent on inducer-specific helical phasing relationships between transcription factor binding sites. We also show that the transcriptional activity of CBP/p300 is potentiated by mycobacterial stimulation of monocytes. The identification of TNF-alpha regulatory elements and coactivators involved in M. tuberculosis-stimulated gene expression thus provides potential selective molecular targets in the modulation of TNF-alpha gene expression in the setting of mycobacterial infection.
Barthel
Robert
R
The Center for Blood Research. Department of Medicine, Harvard Medical School. The Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Tsytsykova
Alla V
AV
Barczak
Amy K
AK
Tsai
Eunice Y
EY
Dascher
Christopher C
CC
Brenner
Michael B
MB
Goldfeld
Anne E
AE
D051698:Activating Transcription Factor 2; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D050881:E1A-Associated p300 Protein; D051766:Early Growth Response Protein 1; D004797:Enzyme-Linked Immunosorbent Assay; D005404:Fixatives / Q000494:pharmacology; D005557:Formaldehyde / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D017874:Immediate-Early Proteins; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009000:Monocytes / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism / Q000382:microbiology; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D050807:ets-Domain Protein Elk-1
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D002843:Chromatin; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D005404:Fixatives; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D016329:Sp1 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D050807:ets-Domain Protein Elk-1; D005557:Formaldehyde; D008156:Luciferases; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse