Intracellular HIV-1 Tat protein represses constitutive LMP2 transcription increasing proteasome activity by interfering with the binding of IRF-1 to STAT1.
The Tat protein is the transcriptional activator of HIV-1 gene expression, which is not only essential for viral replication, but also important in the complex HIV-induced pathogenesis of AIDS, as both an intracellular and an extracellular released protein. Accordingly, Tat is able to profoundly affect cellular gene expression, regulating several cellular functions, also in non-infected cells. We showed recently that Tat induces modification of immunoproteasomes in that it up-regulates LMP7 (low-molecular-mass polypeptide 7) and MECL1 (multicatalytic endopeptidase complex-like 1) subunits and down-modulates the LMP2 subunit, resulting in a change in the generation and presentation of epitopes in the context of MHC class I. In particular, Tat increases presentation of subdominant and cryptic epitopes. In the present study, we investigated the molecular mechanism responsible for the Tat-induced LMP2 down-regulation and show that intracellular Tat represses transcription of the LMP2 gene by competing with STAT1 (signal transducer and activator of transcription 1) for binding to IRF-1 (interferon-regulatory factor-1) on the overlapping ICS-2 (interferon consensus sequence-2)-GAS (gamma-interferon-activated sequence) present in the LMP2 promoter. This element is constitutively occupied in vivo by the unphosphorylated STAT1-IRF-1 complex, which is responsible for the basal transcription of the gene. Sequestration of IRF-1 by intracellular Tat impairs the formation of the complex resulting in lower LMP2 gene transcription and LMP2 protein expression, which is associated with increased proteolytic activity. On the other hand, extracellular Tat induces the expression of LMP2. These effects of Tat provide another effective mechanism by which HIV-1 affects antigen presentation in the context of the MHC class I complex and may have important implications in the use of Tat for vaccination strategies.
Remoli
Anna L
AL
Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299-Rome 00161, Italy.
Marsili
Giulia
G
Perrotti
Edvige
E
Gallerani
Eleonora
E
Ilari
Ramona
R
Nappi
Filomena
F
Cafaro
Aurelio
A
Ensoli
Barbara
B
Gavioli
Riccardo
R
Battistini
Angela
A
D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004794:Enzyme Repression; D005786:Gene Expression Regulation; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D019169:Jurkat Cells; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
D015696:Gene Products, tat; D050856:Interferon Regulatory Factor-1; D009097:Multienzyme Complexes; D050794:STAT1 Transcription Factor; C071313:LMP-2 protein; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex