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 ILIB transcription from the -59 to +12 ILIB core promoter. These results demonstrate that in contrast to non-viral, enhancer-mediated, transactivation of ILIB, the 1E 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 I1IB, depending on the presence of both IE2 and the Spi-1 TADs. Therefore, the relative expression of 1E I and IE2, which varies during HCMV infection, may provide a molecular mechanism by which IL1B can be repressed, thus, avoiding clearance by the host. (C) 2002 Elsevier Science (USA). All rights reserved.