Histone acetyltransferase (HAT) activity of p300 modulates human T lymphotropic virus type 1 p30II-mediated repression of LTR transcriptional activity.
Human T-lymphotropic virus type-1 (HTLV-1) is a deltaretrovirus that causes adult T cell leukemia/lymphoma, and is implicated in a variety of lymphocyte-mediated inflammatory disorders. HTLV-1 provirus has regulatory and accessory genes in four pX open reading frames. HTLV-1 pX ORF-II encodes two proteins, p13II and p30II, which are incompletely defined in virus replication or pathogenesis. We have demonstrated that pX ORF-II mutations block virus replication in vivo and that ORF-II encoded p30II, a nuclear-localizing protein that binds with CREB-binding protein (CBP)/p300, represses CREB and Tax responsive element (TRE)-mediated transcription. Herein, we have identified p30II motifs important for p300 binding and in regulating TRE-mediated transcription in the absence and presence of HTLV-1 provirus. Within amino acids 100-179 of p30II, a region important for repression of LTR-mediated transcription, we identified a single lysine residue at amino acid 106 (K3) that significantly modulates the ability of p30II to repress TRE-mediated transcription. Exogenous p300, in a dose-responsive manner, reverses p30II-dependent repression of TRE-mediated transcription, in the absence or presence of the provirus, In contrast to wild type p300, p300 HAT mutants (defective in histone acetyltransferase activity) only partially rescued p30(II)-mediated LTR repression. Deacetylation by histone deacetylase-1 (HDAC-1) enhanced p30II-mediated LTR repression, while inhibition of deacetylation by trichostatin A decreases p30(II)-mediated LTR repression. Collectively, our data indicate that HTLV-1 p30II modulates viral gene expression in a cooperative manner with p300-mediated acetylation.
Michael
Bindhu
B
Center for Retrovirus Research and Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA.
Nair
Amrithraj M
AM
Datta
Antara
A
Hiraragi
Hajime
H
Ratner
Lee
L
Lairmore
Michael D
MD
D050882:CREB-Binding Protein / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000502:physiology*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D012191:Retroviridae Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000821:virology; D020079:Terminal Repeat Sequences / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D014764:Viral Proteins / Q000032:analysis / Q000502:physiology*; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D051548:Histone Acetyltransferases; D012191:Retroviridae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014764:Viral Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C072814:tof protein, Human T-lymphotropic virus 1