PDK1 nucleates T cell receptor-induced signaling complex for NF-kappaB activation.
Activation of the transcription factor NF-kappaB after engagement of the T cell receptor (TCR) is important for T cell proliferation and activation during the adaptive immune response. Recent reports have elucidated a signaling pathway that involves the protein kinase C (PKC), the scaffold protein CARD11 (also called CARMA-1), the caspase recruitment domain (CARD)-containing protein Bcl10, and the paracaspase (protease related to caspases) MALT1 as critical intermediates linking the TCR to the IkappaB kinase (IKK) complex. However, the events proximal to the TCR that initiate the activation of this signaling pathway remain poorly defined. We demonstrate that 3-phosphoinositide-dependent kinase 1 (PDK1) has an essential role in this pathway by regulating the activation of PKC and through signal-dependent recruiting of both PKC and CARD11 to lipid rafts. PDK1-associated PKC recruits the IKK complex, whereas PDK1-associated CARD11 recruits the Bcl10-MALT1 complex, thereby allowing activation of the IKK complex through Bcl10-MALT1-dependent ubiquitination of the IKK complex subunit known as NEMO (NF-kappaB essential modifier). Hence, PDK1 plays a critical role by nucleating the TCR-induced NF-kappaB activation pathway in T cells.
Lee
Ki-Young
KY
Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
D'Acquisto
Fulvio
F
Hayden
Matthew S
MS
Shim
Jae-Hyuck
JH
Ghosh
Sankar
S
D064413:3-Phosphoinositide-Dependent Protein Kinases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases; D002460:Cell Line; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D018442:Lymphoma, B-Cell, Marginal Zone / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D014162:Transfection
D064413:3-Phosphoinositide-Dependent Protein Kinases; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D020169:Caspases; D006162:Guanylate Cyclase; D051550:I-kappa B Kinase; D007527:Isoenzymes; D008565:Membrane Proteins; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D017346:Protein Serine-Threonine Kinases; D011948:Receptors, Antigen, T-Cell; C118591:BCL10 protein, human; C491731:IKBKG protein, human; C578562:PDPK1 protein, human; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C076233:PRKCQ protein, human; C400109:MALT1 protein, human; C426242:CARD11 protein, human