Dual regulatory role of human cytomegalovirus immediate-early protein in IL1B transcription is dependent upon Spi-1/PU.1.
Activation of IL1B gene transcription has been shown to play a crucial role in human cytomegalovirus (HCMV) infection. We previously reported that HCMV immediate-early (IE) proteins vigorously transactivate IL1B expression without the need for a normally essential upstream enhancer. This activation appears to depend upon protein-protein tethering between IE2, which provides a transcription activation domain (TAD), and the DNA-binding domain of the transcription factor Spi-1. We now show a distinct mechanism by which IE1 and IE2 mediate both weak Spi-1-independent and vigorous Spi-1-dependent IL1B transcription from the -59 to +12 IL1B core promoter. These results demonstrate that in contrast to non-viral, enhancer-mediated, transactivation of IL1B, the IE mechanism is not absolutely dependent upon Spi-1. However, Spi-1 is required for vigorous transcription. Additionally, we have discovered that IE1, which cooperates with IE2 to transactivate IL1B, has minimal activity in the absence of IE2 and Spi-1. Furthermore, IE1 is a dual-acting factor, which can either activate or repress IL1B, depending on the presence of both IE2 and the Spi-1 TADs. Therefore, the relative expression of IE1 and IE2, which varies during HCMV infection, may provide a molecular mechanism by which IL1B can be repressed, thus, avoiding clearance by the host.
Yang
Zhiyong
Z
The New England Baptist Bone and Joint Institute, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Wara-aswapati
Nawarat
N
Yoshida
Yasuhiro
Y
Walker
Nancy
N
Galson
Deborah L
DL
Listman
James
J
Auron
Philip E
PE
D003587:Cytomegalovirus / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007375:Interleukin-1 / Q000235:genetics*; D008562:Membrane Glycoproteins; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014759:Viral Envelope Proteins; D014764:Viral Proteins; D000099232:Proto-Oncogene Protein Spi-1
D017874:Immediate-Early Proteins; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014759:Viral Envelope Proteins; D014764:Viral Proteins; D000099232:Proto-Oncogene Protein Spi-1; C088645:IE1 protein, cytomegalovirus; C069186:IE2 protein, Cytomegalovirus; C077406:UL115 protein, Human herpesvirus 5; C071440:glycoprotein H, Cytomegalovirus; C499358:glycoprotein H, Human cytomegalovirus; C439068:glycoprotein O, cytomegalovirus