Phosphatase-Dependent Inhibition of NF-κB

Science Signaling  30 Oct 2012:
Vol. 5, Issue 248, pp. ec277
DOI: 10.1126/scisignal.2003736

Activation of the canonical nuclear factor κB (NF-κB) pathway in immune cells mediates cellular differentiation, proliferation, and survival. In T cells in response to signals through receptors such as the T cell receptor (TCR) complex and the tumor necrosis factor–α (TNF-α) receptor (TNFR), the inhibitor of κB (IκB) kinase complex (IKK), which consists of the catalytic α and β subunits, becomes activated and phosphorylates the inhibitor IκB, leading to its degradation and dissociation from NF-κB subunits, which can then translocate to the nucleus to stimulate target gene expression. Aberrant NF-κB signaling in T cells underlies various leukemias and lymphomas (see commentary by Tikhonova and Aifantis). To investigate potential roles for phosphatases in the regulation of NF-κB signaling, Brechmann et al. performed a short-interfering RNA (siRNA)–based screen of a Jurkat T cell line expressing an NF-κB reporter. They found that knockdown of PP4R1, a regulatory subunit of the PP2A family serine and threonine phosphatase PP4c, increased NF-κB activity in response to TCR or TNFR stimulation. Experiments in transfected cells showed that PP4R1 associated with IKKα and IKKβ, and that PP4c was associated with the IKK complex only when PP4R1 was present. Phosphorylation of the activation loop of IKKα and IKKβ in response to TCR stimulation was enhanced in cells lacking PP4R1 compared with that in control cells, and the increased IKK phosphorylation enhanced NF-κB activation. In vitro phosphatase assays showed that IKKα and IKKβ were dephosphorylated in the presence of both PP4R1 and PP4c. Cutaneous T cell lymphomas (CTCLs) are characterized by constitutive NF-κB activation. The authors found that cell lines derived from CTCLs had reduced amounts of PP4R1, and retroviral expression of PP4R1 in one of these cell lines (which had endogenous PP4c) inhibited cellular proliferation. Together, these data suggest that PP4R1 is an inhibitor of NF-κB signaling and that deficiency in PP4R1 is associated with T cell lymphomas.

M. Brechmann, T. Mock, D. Nickles, M. Kiessling, N. Weit, R. Breuer, W. Müller, G. Wabnitz, F. Frey, J. P. Nicolay, N. Booken, Y. Samstag, C.-D. Klemke, M. Herling, M. Boutros, P. H. Krammer, R. Arnold, A PP4 holoenzyme balances physiological and oncogenic nuclear factor-kappa B signaling in T lymphocytes. Immunity 37, 697–708 (2012). [PubMed]

A. Tikhonova, I. Aifantis, The taming of the NF-κB: PP4R1 navigates while PP4c dephosphorylates. Immunity 37, 594–596 (2012). [PubMed]