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 (γ-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.
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June 2006
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Research Article|
May 15 2006
Intracellular HIV-1 Tat protein represses constitutive LMP2 transcription increasing proteasome activity by interfering with the binding of IRF-1 to STAT1
Anna L. Remoli;
Anna L. Remoli
1
*Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299 – Rome 00161, Italy
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Giulia Marsili;
Giulia Marsili
1
*Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299 – Rome 00161, Italy
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Edvige Perrotti;
Edvige Perrotti
1
*Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299 – Rome 00161, Italy
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Eleonora Gallerani;
Eleonora Gallerani
†Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy
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Ramona Ilari;
Ramona Ilari
*Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299 – Rome 00161, Italy
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Filomena Nappi;
Filomena Nappi
*Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299 – Rome 00161, Italy
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Aurelio Cafaro;
Aurelio Cafaro
*Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299 – Rome 00161, Italy
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Barbara Ensoli;
Barbara Ensoli
*Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299 – Rome 00161, Italy
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Riccardo Gavioli;
Riccardo Gavioli
†Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy
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Angela Battistini
Angela Battistini
2
*Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299 – Rome 00161, Italy
2To whom correspondence should be addressed (email battist@iss.it).
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Publisher: Portland Press Ltd
Received:
September 23 2005
Revision Received:
March 02 2006
Accepted:
March 03 2006
Accepted Manuscript online:
March 03 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 396 (2): 371–380.
Article history
Received:
September 23 2005
Revision Received:
March 02 2006
Accepted:
March 03 2006
Accepted Manuscript online:
March 03 2006
Connected Content
A commentary has been published:
HIV Tat-mediated transcriptional regulation of proteasome protein cleavage specificity
Citation
Anna L. Remoli, Giulia Marsili, Edvige Perrotti, Eleonora Gallerani, Ramona Ilari, Filomena Nappi, Aurelio Cafaro, Barbara Ensoli, Riccardo Gavioli, Angela Battistini; Intracellular HIV-1 Tat protein represses constitutive LMP2 transcription increasing proteasome activity by interfering with the binding of IRF-1 to STAT1. Biochem J 1 June 2006; 396 (2): 371–380. doi: https://doi.org/10.1042/BJ20051570
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