A PP4 holoenzyme balances physiological and oncogenic nuclear factor-kappa B signaling in T lymphocytes

Immunity. 2012 Oct 19;37(4):697-708. doi: 10.1016/j.immuni.2012.07.014.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biocatalysis
  • Cell Differentiation
  • Cells, Cultured
  • Holoenzymes / immunology
  • Humans
  • I-kappa B Kinase / immunology
  • I-kappa B Kinase / metabolism
  • Lymphocyte Activation
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / immunology*
  • RNA Interference
  • Signal Transduction*
  • T-Lymphocytes / immunology*


  • Holoenzymes
  • NF-kappa B
  • I-kappa B Kinase
  • Phosphoprotein Phosphatases
  • protein phosphatase 4