A PP4 Holoenzyme Balances Physiological and Oncogenic Nuclear Factor-Kappa B Signaling in T Lymphocytes

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• 作者：Markus Brechmann ; Thomas Mock ; Dorothee Nickles ; Michael Kiessling ; Nicole Weit ; Rebecca Breuer ; Wolfgang M¨¹ller ; Guido Wabnitz ; Felice Frey ; Jan?P. Nicolay ; Nina Booken ; Yvonne Samstag ; Claus-Detlev Klemke ; Marco Herling ; Michael Boutros ; Peter?H. Krammer ; R¨¹diger Arnold
• 刊名：Immunity
• 出版年：2012
• 出版时间：19 October, 2012
• 年：2012
• 卷：37
• 期：4
• 页码：697-708
• 全文大小：2126 K

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Summary

Signal transduction to nuclear factor-kappa B (NF-¦ÊB) 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-¦ÊB activity in T lymphocytes. PP4R1 formed part of a distinct PP4 holoenzyme and bridged the inhibitor of NF-¦ÊB 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-¦ÊB signaling in NF-¦ÊB-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-¦ÊB signaling in a subgroup of T?cell lymphomas.