The Protein Phosphatase 2A Regulatory Subunit B56γ Mediates Suppression of T Cell Receptor (TCR)-induced Nuclear Factor-κB (NF-κB) Activity

Breuer, Rebecca J.; Becker, Michael; Brechmann, Markus; Möck, Thomas; Arnold, Rüdiger; Krammer, Peter H.

doi:10.1074/jbc.m113.533547

Cited by 34 publications

(31 citation statements)

References 39 publications

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“…This observation may very well point at cell type‐specific effects of PP1. It is plausible that the T cell‐specific effect of PP1 is regulated by PPP1R11, similarly to the recently uncovered role of the PP2A regulatory subunit B56γ in mediating specific effects upon TCR stimulation . Parallel studies to understand the effect of PPP1R11 on multiple immune (and other) cells from the same mouse model or human samples are warranted to further confirm the applicability of our findings.…”

Section: Discussionsupporting

confidence: 75%

“…Hence, it cannot be excluded that depending on the cell type, the tautomycetin‐induced effect on the measured cytokines could also be in part mediated by PP2A in addition to PP1. This needs to be considered especially because PP2A itself is implicated in NF‐κB signaling in T cells . Importantly, our novel results revealing a role of PPP1R11 in TCR‐induced cytokine activation may allow for a more specific targeting of PP1A activity in T cells.…”

Section: Discussionmentioning

confidence: 91%

“…This needs to be considered especially because PP2A itself is implicated in NF-B signaling in T cells. 74 Importantly, our novel results revealing a role of PPP1R11 in TCR-induced cytokine activation may allow for a more specific targeting of PP1A activity in T cells. In stark contrast to the role of PP1 in T cells as shown in the above literature and indicated by our study, PP1 has been shown to negatively regulate pro-inflammatory cytokine production in macrophages by inhibiting MAPK and NF-B pathways.…”

Section: Inhibition Of Pp1 Attenuates Pro-inflammatory Cytokine Exprementioning

confidence: 90%

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Phosphatase inhibitor PPP1R11 modulates resistance of human T cells toward Treg-mediated suppression of cytokine expression

Joshi

Fernandes

Shang

et al. 2019

Journal of Leukocyte Biology

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Regulatory T cells (Tregs) act as indispensable unit for maintaining peripheral immune tolerance mainly by regulating effector T cells. T cells resistant to suppression by Tregs pose therapeutic challenges in the treatment of autoimmune diseases, while augmenting susceptibility to suppression may be desirable for cancer therapy. To understand the cell intrinsic signals in T cells during suppression by Tregs, we have previously performed a global phosphoproteomic characterization. We revealed altered phosphorylation of protein phosphatase 1 regulatory subunit 11 (PPP1R11; Inhibitor‐3) in conventional T cells upon suppression by Tregs. Here, we show that silencing of PPP1R11 renders T cells resistant toward Treg‐mediated suppression of TCR‐induced cytokine expression. Furthermore, whole‐transcriptome sequencing revealed that PPP1R11 differentially regulates not only the expression of specific T cell stimulation‐induced cytokines but also other molecules and pathways in T cells. We further confirmed the target of PPP1R11, PP1, to augment TCR‐induced cytokine expression. In conclusion, we present PPP1R11 as a novel negative regulator of T cell activation‐induced cytokine expression. Targeting PPP1R11 may have therapeutic potential to regulate the T cell activation status including modulating the susceptibility of T cells toward Treg‐mediated suppression, specifically altering the stimulation‐induced T cell cytokine milieu.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 91%

Section: Inhibition Of Pp1 Attenuates Pro-inflammatory Cytokine Exprementioning

confidence: 90%

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Phosphatase inhibitor PPP1R11 modulates resistance of human T cells toward Treg-mediated suppression of cytokine expression

Joshi

Fernandes

Shang

et al. 2019

Journal of Leukocyte Biology

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“…In vivo assays (Arnold and Sears, 2006;Margolis et al, 2006;Rodgers et al, 2011;Breuer et al, 2014) support a general pattern of substrate specificity for mammalian B56 isoforms. We used selection analysis to detect evolutionary evidence of functional diversification within PP2A gene families.…”

Section: The B56 Gene Family Has Undergone Positive Selection In Bothmentioning

confidence: 99%

Atypical Protein Phosphatase 2A Gene Families Do Not Expand via Paleopolyploidization

Booker

DeLong

2016

Plant Physiol.

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Protein phosphatase 2A (PP2A) presents unique opportunities for analyzing molecular mechanisms of functional divergence between gene family members. The canonical PP2A holoenzyme regulates multiple eukaryotic signaling pathways by dephosphorylating target proteins and contains a catalytic (C) subunit, a structural/scaffolding (A) subunit, and a regulatory (B) subunit. Genes encoding PP2A subunits have expanded into multigene families in both flowering plants and mammals, and the extent to which different isoform functions may overlap is not clearly understood. To gain insight into the diversification of PP2A subunits, we used phylogenetic analyses to reconstruct the evolutionary histories of PP2A gene families in Arabidopsis (Arabidopsis thaliana). Genes encoding PP2A subunits in mammals represent ancient lineages that expanded early in vertebrate evolution, while flowering plant PP2A subunit lineages evolved much more recently. Despite this temporal difference, our data indicate that the expansion of PP2A subunit gene families in both flowering plants and animals was driven by whole-genome duplications followed by nonrandom gene loss. Selection analysis suggests that the expansion of one B subunit gene family (B56/PPP2R5) was driven by functional diversification rather than by the maintenance of gene dosage. We also observed reduced expansion rates in three distinct B subunit subclades. One of these subclades plays a highly conserved role in cell division, while the distribution of a second subclade suggests a specialized function in supporting beneficial microbial associations. Thus, while whole-genome duplications have driven the expansion and diversification of most PP2A gene families, members of functionally specialized subclades quickly revert to singleton status after duplication events.

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“…NF-kB is an important transcriptional factor that regulates many cellular and organismal processes including immune and inflammatory responses, cellular growth, and survival (10). NF-kB is a complex composed of two subunits designated p50 and RelA/p65, and is activated by several inflammatory cytokines including TNFα, which leads to IKK activation (11). In turn, IKK phosphorylates IkB proteins.…”

mentioning

confidence: 99%

Regulation of NF-kB Signalling Through the PR55β-RelA Interaction in Osteoblasts

Suzuki

Sugiyama

Ohyama

et al. 2020

In Vivo

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Background/Aim: Nuclear factor kappa B (NF-kB) signalling including the RelA subunit is activated upon fibroblast growth factor (FGF) stimulation. A clear understanding of the mechanisms underlying this action will provide insights into molecular targeting therapy. Furthermore, protein phosphatase 2A (PP2A) is involved in RelA dephosphorylation, but little is known about the underlying mechanism. Materials and Methods: Because the regulatory subunits of PP2A drive NF-kB signalling via RelA, we used qRT-PCR and immunoblot analysis to investigate the expression of these subunits in MC3T3-E1 cells. We examined weather FGF2 interacts with NF-kB using immunocytochemistry (IC), immunoprecipitation (IP), and pull-down assay (PD) using recombinant proteins. Results: PR55β expression was increased, whereas activated RelA was dephosphorylated upon FGF2 stimulation. Further, the interaction of PR55β with RelA was confirmed by IC, IP, and PD. Conclusion: FGF2-induced PR55β directly interacts with RelA and regulates NF-kB signalling.

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The Protein Phosphatase 2A Regulatory Subunit B56γ Mediates Suppression of T Cell Receptor (TCR)-induced Nuclear Factor-κB (NF-κB) Activity

Cited by 34 publications

References 39 publications

Phosphatase inhibitor PPP1R11 modulates resistance of human T cells toward Treg-mediated suppression of cytokine expression

Phosphatase inhibitor PPP1R11 modulates resistance of human T cells toward Treg-mediated suppression of cytokine expression

Atypical Protein Phosphatase 2A Gene Families Do Not Expand via Paleopolyploidization

Regulation of NF-kB Signalling Through the PR55β-RelA Interaction in Osteoblasts

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