HIV Tat-mediated transcriptional regulation of proteasome protein cleavage specificity.
The major antigen-adapted immune response protecting a vertebrate against virus infection is that mediated by CTLs (cytotoxic T-lymphocytes). CTLs destroy virus-infected cells, thereby containing the infection. They are activated by recognition of peptide antigens or epitopes, presented to them in the context of MHC I proteins. These epitopes are derived from proteolytic degradation of endogenously synthesized proteins, which is mediated by the proteasome. Augmentation of epitope presentation by MHC I is thought to be effected by the immunoproteasome, induced in response to IFN-gamma (interferon-gamma) in some cells, and constitutively expressed in others. In this issue of the Biochemical Journal, Remoli and colleagues describe the manipulation of the immunoproteasome by the Tat (transcriptional activation) protein of HIV. The authors show that Tat deregulates the balance of the three proteins, LMP2 (low-molecular-mass polypeptide 2), LMP7 and MECL1 (multicatalytic endopeptidase complex-like 1), which distinguish the immunoproteasome from the proteasome, and they provide a molecular explanation. Intracellular Tat sequesters IRF-1 (interferon-regulatory factor-1) from its cognate promoter element, where normally it associates with STAT1 (signal transducer and activator of transcription 1) to activate basal transcription of the LMP2 gene. LMP2 expression is inhibited as a consequence, skewing the stoichiometry of the immunoproteasome and changing its enzymatic activity. These findings provide a molecular account of an immunomodulatory activity of HIV: changing the peptide antigen profile of cells expressing or exposed to Tat. They may also provide an avenue for manipulating vaccine efficacy and specificity with Tat-based adjuvants.
Aresté
Cristina
C
Cancer Research UK Institute for Cancer Studies, University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.
Blackbourn
David J
DJ
D003546:Cysteine Endopeptidases / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000494:pharmacology*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic
D015696:Gene Products, tat; D050856:Interferon Regulatory Factor-1; D050794:STAT1 Transcription Factor; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex