Proliferating cell nuclear antigen as the cell cycle sensor for an HLA-derived peptide blocking T cell proliferation.
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.
Ling
X
X
Department of Pediatrics, Cardiothoracic Surgery, and Pathology, Stanford University, CA 94305, USA.
Kamangar
S
S
Boytim
M L
ML
Kelman
Z
Z
Huie
P
P
Lyu
S C
SC
Sibley
R K
RK
Hurwitz
J
J
Clayberger
C
C
Krensky
A M
AM
D002453:Cell Cycle / Q000276:immunology*; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors; D004261:DNA Replication / Q000276:immunology; D006683:HLA-DQ Antigens / Q000378:metabolism / Q000494:pharmacology*; D059848:HLA-DQ alpha-Chains; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D020798:Two-Hybrid System Techniques
D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D007166:Immunosuppressive Agents; D008024:Ligands; D010446:Peptide Fragments; D018809:Proliferating Cell Nuclear Antigen; D016160:Retinoblastoma Protein; D004258:DNA Polymerase III