Inhibition of CTLA-4 function by the regulatory subunit of serine/threonine phosphatase 2A.
The catalytic subunit of the serine/threonine phosphatase 2A (PP2A) can interact with the cytoplasmic tail of CTLA-4. However, the molecular basis and the biological significance of this interaction are unknown. In this study, we report that the regulatory subunit of PP2A (PP2AA) also interacts with the cytoplasmic tail of CTLA-4. Interestingly, TCR ligation induces tyrosine phosphorylation of PP2AA and its dissociation from CTLA-4 when coligated. The association between PP2AA and CTLA-4 involves a conserved three-lysine motif in the juxtamembrane portion of the cytoplasmic tail of CTLA-4. Mutations of these lysine residues prevent the binding of PP2AA and enhance the inhibition of IL-2 gene transcription by CTLA-4, indicating that PP2A represses CTLA-4 function. Our data imply that the lysine-rich motif in CTLA-4 may be used to identify small molecules that block its binding to PP2A and act as agonists for CTLA-4 function.
Baroja
Miren L
ML
Transplantation and Immunobiology Group, John P. Robarts Research Institute, University of Western Ontario, 100 Perth Drive, London, Ontario N6A 5K8, Canada.
Vijayakrishnan
Lalitha
L
Bettelli
Estelle
E
Darlington
Peter J
PJ
Chau
Thu A
TA
Ling
Vincent
V
Collins
Mary
M
Carreno
Beatriz M
BM
Madrenas
Joaquín
J
Kuchroo
Vijay K
VK
D000069594:Abatacept; D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D060908:CTLA-4 Antigen; D002461:Cell Line, Transformed; D003593:Cytoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D019169:Jurkat Cells; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010749:Phosphoprotein Phosphatases / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D054648:Protein Phosphatase 2; D017434:Protein Structure, Tertiary / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D008024:Ligands; C432785:PPP2R1B protein, human; C086766:Ppp2r1b protein, mouse; D011948:Receptors, Antigen, T-Cell; D000069594:Abatacept; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D008239:Lysine