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 described a signaling pathway that involves the kinase PKCtheta, the scaffold protein CARD11 (also called CARMA-1), the CARD-domain containing protein BcMO, and the paracaspase (protease related to caspases) MALT1 as critical intermediates linking the TCR to the IkappaB kinase (IKK) complex. However, the exact sequence of events that occurs following the activation of this signaling pathway remains poorly defined. We have recently demonstrated that 3-phosphoinositide-dependent kinase 1 (PDK1) has an essential role in this pathway by regulating the activation of PKCtheta and through signal-dependent recruiting of both PKCtheta and CARD11 to lipid rafts. PDK1-associated PKCq recruits the IKKcomplex, 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. Hence, PDK1 plays a critical role by nucleating the TCR-induced NF-kappaB activation pathway in T cells. In this proposal we will further extend our observations to better understand exactly how PDK-1 recruits PKCtheta and CARD11. We will identify the domains involved in these interactions and use the knowledge from these studies to devise novel approaches for suppressing T-cell activation. In addition we have also found that PKCtheta is involved in the activation of LFA1 following TCR-engagement through an inside-out pathway. We will establish the importance of this pathway by generating novel genetic models that we believe will dissociate the ability of PKCtheta to function as an adapter for recruitment of IKK, from its ability to promote stable conjugation and immunological synapses through its effect on LFA1. We believe that these studies will both provide a fuller understanding of a key cellular pathway, and the opportunity to develop novel approaches for immunosuppression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI068977-06
Application #
7754644
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Mallia, Conrad M
Project Start
2006-02-01
Project End
2012-12-31
Budget Start
2010-02-01
Budget End
2012-12-31
Support Year
6
Fiscal Year
2010
Total Cost
$375,081
Indirect Cost
Name
Columbia University (N.Y.)
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Oh, Hyunju; Grinberg-Bleyer, Yenkel; Liao, Will et al. (2017) An NF-?B Transcription-Factor-Dependent Lineage-Specific Transcriptional Program Promotes Regulatory T Cell Identity and Function. Immunity 47:450-465.e5
Grinberg-Bleyer, Yenkel; Oh, Hyunju; Desrichard, Alexis et al. (2017) NF-?B c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer. Cell 170:1096-1108.e13
Postler, Thomas S; Pantry, Shara N; Desrosiers, Ronald C et al. (2017) Identification and characterization of a long non-coding RNA up-regulated during HIV-1 infection. Virology 511:30-39
Dainichi, Teruki; Hayden, Matthew S; Park, Sung-Gyoo et al. (2016) PDK1 Is a Regulator of Epidermal Differentiation that Activates and Organizes Asymmetric Cell Division. Cell Rep 15:1615-23
Yu, Minjun; Owens, David M; Ghosh, Sankar et al. (2015) Conditional PDK1 Ablation Promotes Epidermal and T-Cell-Mediated Dysfunctions Leading to Inflammatory Skin Disease. J Invest Dermatol 135:2688-2696
Grinberg-Bleyer, Yenkel; Dainichi, Teruki; Oh, Hyunju et al. (2015) Cutting edge: NF-?B p65 and c-Rel control epidermal development and immune homeostasis in the skin. J Immunol 194:2472-6
Hayden, Matthew S; Ghosh, Sankar (2014) Regulation of NF-?B by TNF family cytokines. Semin Immunol 26:253-66
Kang, Jung-Ah; Jeong, Sang Phil; Park, Daeho et al. (2013) Transition from heterotypic to homotypic PDK1 homodimerization is essential for TCR-mediated NF-?B activation. J Immunol 190:4508-15
Park, Sung-Gyoo; Long, Meixiao; Kang, Jung-Ah et al. (2013) The kinase PDK1 is essential for B-cell receptor mediated survival signaling. PLoS One 8:e55378
Oh, Hyunju; Ghosh, Sankar (2013) NF-ýýB: roles and regulation in different CD4(+) T-cell subsets. Immunol Rev 252:41-51

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