Publication: Sequential cleavage by metallopeptidases and proteasomes is involved in processing HIV-1 ENV epitope for endogenous MHC class I antigen presentation.
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2000-05-15
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Abstract
Antigenic peptides derived from viral proteins by multiple proteolytic cleavages are bound by MHC class I molecules and recognized by CTL. Processing predominantly takes place in the cytosol of infected cells by the action of proteasomes. To identify other proteases involved in the endogenous generation of viral epitopes, specifically those derived from proteins routed to the secretory pathway, we investigated presentation of the HIV-1 ENV 10-mer epitope 318RGPGRAFVTI327 (p18) to specific CTL in the presence of diverse protease inhibitors. Both metalloproteinase and proteasome inhibitors decreased CTL recognition of the p18 epitope expressed from either native gp160 or from a chimera based on the hepatitis B virus secretory core protein as carrier protein. Processing of this epitope from both native ENV and the hepatitis B virus secretory core chimeric protein appeared to proceed by a TAP-dependent pathway that involved sequential cleavage by proteasomes and metallo-endopeptidases; however, other protease activities could replace the function of the lactacystin-sensitive proteasomes. By contrast, in a second TAP-independent pathway we detected no contribution of metallopeptidases for processing the ENV epitope from the chimeric protein. These results show that, in the classical TAP-dependent MHC class I pathway, endogenous Ag processing of viral proteins to yield the p18 10-mer epitope requires metallo-endopeptidases in addition to proteasomes.
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Antigen Presentation ATP Binding Cassette Transporter, Subfamily B, Member 2 ATP-Binding Cassette Transporters Acetylcysteine Animals Cell Line, Transformed Cysteine Endopeptidases Cysteine Proteinase Inhibitors Epitopes, T-Lymphocyte HIV Envelope Protein gp160 HIV-1 Hepatitis B e Antigens Histocompatibility Antigens Class I Humans Hydrolysis Leupeptins Metalloendopeptidases Mice Mice, Inbred BALB C Multienzyme Complexes Pepstatins Peptide Fragments Proteasome Endopeptidase Complex Protein Processing, Post-Translational Recombinant Fusion Proteins Signal Transduction T-Lymphocytes, Cytotoxic
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J Immunol . 2000 May 15;164(10):5070-7