A PP4 holoenzyme balances physiological and oncogenic nuclear factor-kappa B signaling in T lymphocytes.
Signal transduction to nuclear factor-kappa B (NF-κB) involves multiple kinases and phosphorylated target proteins, but little is known about signal termination by dephosphorylation. By RNAi screening, we have identified protein phosphatase 4 regulatory subunit 1 (PP4R1) as a negative regulator of NF-κB activity in T lymphocytes. PP4R1 formed part of a distinct PP4 holoenzyme and bridged the inhibitor of NF-κB kinase (IKK) complex and the phosphatase PP4c, thereby directing PP4c activity to dephosphorylate and inactivate the IKK complex. PP4R1 expression was triggered upon activation and proliferation of primary human T lymphocytes and deficiency for PP4R1 caused sustained and increased IKK activity, T cell hyperactivation, and aberrant NF-κB signaling in NF-κB-addicted T cell lymphomas. Collectively, our results unravel PP4R1 as a previously unknown activation-associated negative regulator of IKK activity in lymphocytes whose downregulation promotes oncogenic NF-κB signaling in a subgroup of T cell lymphomas.
Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
Markus
M
Brechmann
Thomas
T
Mock
Dorothee
D
Nickles
Michael
M
Kiessling
Nicole
N
Weit
Rebecca
R
Breuer
Wolfgang
W
Müller
Guido
G
Wabnitz
Felice
F
Frey
Jan P
JP
Nicolay
Nina
N
Booken
Yvonne
Y
Samstag
Claus-Detlev
CD
Klemke
Marco
M
Herling
Michael
M
Boutros
Peter H
PH
Krammer
Rüdiger
R
Arnold
D055162:Biocatalysis; D002454:Cell Differentiation; D002478:Cells, Cultured; D020035:Holoenzymes / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000276:immunology*; D034622:RNA Interference; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
D020035:Holoenzymes; D016328:NF-kappa B; D051550:I-kappa B Kinase; D010749:Phosphoprotein Phosphatases; C080406:protein phosphatase 4