TY  - GEN
ID  - heidok11085
AV  - public
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/11085/
KW  - T Lymphozyt 
KW  -  Phosphatase 
KW  -  NF-kappaB 
KW  -  Signaltransduktion 
KW  -  RNAiT lymphocyte 
KW  -  phosphatase 
KW  -  NF-kappaB 
KW  -  signaling 
KW  -  RNAi
Y1  - 2010///
N2  - The transcription factor nuclear factor-kappaB (NF-kappaB) plays a key role in the immune system by controlling lymphocyte survival and activation. Conversely, aberrant NF-kappaB activity has been implicated in several lymphoid malignancies and contributes to a variety of autoimmune disorders. While multiple kinases and phosphorylated target proteins that induce NF-kappaB activity have been identified, the molecular machinery involved in the termination of antigen receptor-mediated NF-kappaB activation is only partially understood. Since signal transduction from activated receptors to NF-kappaB largely relies on phosphorylation events, phosphatases are expected to play a major role in the modulation and termination of NF-kappaB activity. Therefore, the current study aimed at systematically defining phosphatases that are involved in T cell receptor (TCR)-induced NF-kappaB signaling. To this end, an RNA interference (RNAi) genetic screen has been adopted based on a novel NF-kappaB-dependent reporter system. Using this approach, several NF-kappaB-modulating phosphatases were identified among which the protein phosphatase 4 regulatory subunit 1 (PP4R1) was confirmed as a central negative regulator of NF-kappaB activity in T lymphocytes. PP4R1 expression is strongly upregulated in primary human T lymphocytes upon activation. PP4R1 specifically binds to the inhibitor of NF-kappaB kinase alpha (IKKalpha) and the catalytic subunit PP4c, thereby directing PP4c phosphatase activity to dephosphorylate and inactivate the IKK complex. Accordingly, PP4R1 silencing causes sustained and increased IKK activity and T cell hyperactivation as reflected by enhanced induction of NF-kappaB target genes and secretion of cytokines. Conversely, PP4R1 overexpression significantly impairs NF-kappaB activation upon TCR stimulation, but does not affect AP-1 signaling. Furthermore, PP4R1 was found to be downregulated in a subset of malignant T lymphocytes derived from patients with Sézary syndrome, a severe form of cutaneous T cell lymphoma (CTCL). PP4R1 deficiency causes constitutive IKK/NF-kappaB signaling and is required for survival of NF-kappaB-addicted CTCL cells. In summary, the present work identified PP4R1 as a central gatekeeper of IKK activity and as a suppressor of T cell activation and lymphoma survival. These findings expand our current knowledge of NF-kappaB signal transduction and contribute to a more precise molecular understanding of NF-kappaB regulation in health and disease. 
A1  - Brechmann, Markus
TI  - Identification and Characterization of Protein Phosphatase 4 Regulatory Subunit 1 (PP4R1) as a Suppressor of NF-kappaB in T Lymphocytes and T Cell Lymphomas
ER  -