A PP4 holoenzyme balances physiological and oncogenic nuclear factor-kappa B signaling in T lymphocytes
|Authors:||Brechmann M, Mock T, Nickles D, Kiessling M, Weit N, Breuer R, Müller W, Wabnitz G, Frey F, Nicolay JP, Booken N, Samstag Y, Klemke CD, Herling M, Boutros M, Krammer PH, Arnold R|
|CellNetworks People:||Boutros Michael|
|Journal:||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.