Abstract
Synthetic peptides corresponding to structural regions of HLA molecules are novel immunosuppressive agents. A peptide corresponding to residues 65-79 of the alpha-chain of HLA-DQA03011 (DQ65-79) blocks cell cycle progression from early G1 to the G1 restriction point, which inhibits cyclin-dependent kinase-2 activity and phosphorylation of the retinoblastoma protein. A yeast two-hybrid screen identified proliferating cell nuclear Ag (PCNA) as a cellular ligand for this peptide, whose interaction with PCNA was further confirmed by in vitro biochemistry. Electron microscopy demonstrates that the DQ65-79 peptide enters the cell and colocalizes with PCNA in the T cell nucleus in vivo. Binding of the DQ65-79 peptide to PCNA did not block polymerase delta (pol delta)-dependent DNA replication in vitro. These findings support a key role for PCNA as a sensor of cell cycle progression and reveal an unanticipated function for conserved regions of HLA molecules.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Cell Cycle / immunology*
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DNA Polymerase III / antagonists & inhibitors
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DNA Replication / immunology
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HLA-DQ Antigens / metabolism
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HLA-DQ Antigens / pharmacology*
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HLA-DQ alpha-Chains
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Humans
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Immunosuppressive Agents / chemical synthesis
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Immunosuppressive Agents / metabolism
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Immunosuppressive Agents / pharmacology*
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Ligands
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Lymphocyte Activation / immunology*
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Peptide Fragments / chemical synthesis
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Peptide Fragments / immunology*
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Peptide Fragments / metabolism
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Peptide Fragments / pharmacology*
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Phosphorylation
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Proliferating Cell Nuclear Antigen / metabolism*
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Retinoblastoma Protein / antagonists & inhibitors
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Retinoblastoma Protein / metabolism
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Two-Hybrid System Techniques
Substances
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HLA-DQ Antigens
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HLA-DQ alpha-Chains
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HLA-DQA1 antigen
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Immunosuppressive Agents
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Ligands
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Peptide Fragments
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Proliferating Cell Nuclear Antigen
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Retinoblastoma Protein
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DNA Polymerase III