A molecular mechanism for human T-cell leukemia virus latency and Tax transactivation.
The human T-cell leukemia virus type I (HTLV-I) is the causative agent of an aggressive T-cell malignancy in humans. While the virus appears to maintain a state of latency in most infected cells, high level virion production is an essential step in the HTLV-I life cycle. The virally-encoded Tax protein, a potent activator of gene expression, is believed to control the switch from latency to replication. Tax stimulation of HTLV-I transcription is mediated through cellular activating transcription factor/cAMP response element binding proteins, which bind the three 21-base pair (bp) repeat viral enhancer elements. In this report, we show that viral latency may result from a highly unstable interaction between CREB and the HTLV-I 21-bp repeats, resulting in rapid dissociation of CREB from the viral promoter. In the presence Tax, the dissociation rate of CREB from a 21-bp repeat element is decreased. This stabilization is highly specific, requiring the amino-terminal region of CREB and appropriate 21-bp repeat sequences. We suggest that Tax stabilization of CREB binding to the viral promoter leads to an increase in gene expression, possibly providing the switch from latency to high level replication of the virus.
Brauweiler
A
A
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins 80523, USA.
Garl
P
P
Franklin
A A
AA
Giebler
H A
HA
Nyborg
J K
JK
D051698:Activating Transcription Factor 2; D001483:Base Sequence; D001665:Binding Sites; D016384:Consensus Sequence; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004279:DNA, Viral / Q000378:metabolism; D016356:Gene Products, tax / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics* / Q000254:growth & development; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D011485:Protein Binding; D012091:Repetitive Sequences, Nucleic Acid; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D017735:Virus Latency / Q000235:genetics*
D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D004279:DNA, Viral; D016356:Gene Products, tax; D014157:Transcription Factors