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CKIP-1 Is an Intrinsic Negative Regulator of T-Cell Activation through an Interaction with CARMA1
The transcription factor NF-κB plays a key regulatory role in lymphocyte activation and generation of immune response. Stimulation of T cell receptor (TCR) induces phosphorylation of CARMA1 by PKCθ, resulting in formation of CARMA1-Bcl10-MALT1 (CBM) complex at lipid rafts and subsequently leading to...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894987/ https://www.ncbi.nlm.nih.gov/pubmed/24465689 http://dx.doi.org/10.1371/journal.pone.0085762 |
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author | Sakamoto, Takashi Kobayashi, Masayuki Tada, Kohei Shinohara, Masanobu Io, Katsuhiro Nagata, Kayoko Iwai, Fumie Takiuchi, Yoko Arai, Yasuyuki Yamashita, Kouhei Shindo, Keisuke Kadowaki, Norimitsu Koyanagi, Yoshio Takaori-Kondo, Akifumi |
author_facet | Sakamoto, Takashi Kobayashi, Masayuki Tada, Kohei Shinohara, Masanobu Io, Katsuhiro Nagata, Kayoko Iwai, Fumie Takiuchi, Yoko Arai, Yasuyuki Yamashita, Kouhei Shindo, Keisuke Kadowaki, Norimitsu Koyanagi, Yoshio Takaori-Kondo, Akifumi |
author_sort | Sakamoto, Takashi |
collection | PubMed |
description | The transcription factor NF-κB plays a key regulatory role in lymphocyte activation and generation of immune response. Stimulation of T cell receptor (TCR) induces phosphorylation of CARMA1 by PKCθ, resulting in formation of CARMA1-Bcl10-MALT1 (CBM) complex at lipid rafts and subsequently leading to NF-κB activation. While many molecular events leading to NF-κB activation have been reported, it is less understood how this activation is negatively regulated. We performed a cell-based screening for negative regulators of TCR-mediated NF-κB activation, using mutagenesis and complementation cloning strategies. Here we show that casein kinase-2 interacting protein-1 (CKIP-1) suppresses PKCθ-CBM-NF-κB signaling. We found that CKIP-1 interacts with CARMA1 and competes with PKCθ for association. We further confirmed that a PH domain of CKIP-1 is required for association with CARMA1 and its inhibitory effect. CKIP-1 represses NF-κB activity in unstimulated cells, and inhibits NF-κB activation induced by stimulation with PMA or constitutively active PKCθ, but not by stimulation with TNFα. Interestingly, CKIP-1 does not inhibit NF-κB activation induced by CD3/CD28 costimulation, which caused dissociation of CKIP-1 from lipid rafts. These data suggest that CKIP-1 contributes maintenance of a resting state on NF-κB activity or prevents T cells from being activated by inadequate signaling. In conclusion, we demonstrate that CKIP-1 interacts with CARMA1 and has an inhibitory effect on PKCθ-CBM-NF-κB signaling. |
format | Online Article Text |
id | pubmed-3894987 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-38949872014-01-24 CKIP-1 Is an Intrinsic Negative Regulator of T-Cell Activation through an Interaction with CARMA1 Sakamoto, Takashi Kobayashi, Masayuki Tada, Kohei Shinohara, Masanobu Io, Katsuhiro Nagata, Kayoko Iwai, Fumie Takiuchi, Yoko Arai, Yasuyuki Yamashita, Kouhei Shindo, Keisuke Kadowaki, Norimitsu Koyanagi, Yoshio Takaori-Kondo, Akifumi PLoS One Research Article The transcription factor NF-κB plays a key regulatory role in lymphocyte activation and generation of immune response. Stimulation of T cell receptor (TCR) induces phosphorylation of CARMA1 by PKCθ, resulting in formation of CARMA1-Bcl10-MALT1 (CBM) complex at lipid rafts and subsequently leading to NF-κB activation. While many molecular events leading to NF-κB activation have been reported, it is less understood how this activation is negatively regulated. We performed a cell-based screening for negative regulators of TCR-mediated NF-κB activation, using mutagenesis and complementation cloning strategies. Here we show that casein kinase-2 interacting protein-1 (CKIP-1) suppresses PKCθ-CBM-NF-κB signaling. We found that CKIP-1 interacts with CARMA1 and competes with PKCθ for association. We further confirmed that a PH domain of CKIP-1 is required for association with CARMA1 and its inhibitory effect. CKIP-1 represses NF-κB activity in unstimulated cells, and inhibits NF-κB activation induced by stimulation with PMA or constitutively active PKCθ, but not by stimulation with TNFα. Interestingly, CKIP-1 does not inhibit NF-κB activation induced by CD3/CD28 costimulation, which caused dissociation of CKIP-1 from lipid rafts. These data suggest that CKIP-1 contributes maintenance of a resting state on NF-κB activity or prevents T cells from being activated by inadequate signaling. In conclusion, we demonstrate that CKIP-1 interacts with CARMA1 and has an inhibitory effect on PKCθ-CBM-NF-κB signaling. Public Library of Science 2014-01-17 /pmc/articles/PMC3894987/ /pubmed/24465689 http://dx.doi.org/10.1371/journal.pone.0085762 Text en © 2014 Sakamoto et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Sakamoto, Takashi Kobayashi, Masayuki Tada, Kohei Shinohara, Masanobu Io, Katsuhiro Nagata, Kayoko Iwai, Fumie Takiuchi, Yoko Arai, Yasuyuki Yamashita, Kouhei Shindo, Keisuke Kadowaki, Norimitsu Koyanagi, Yoshio Takaori-Kondo, Akifumi CKIP-1 Is an Intrinsic Negative Regulator of T-Cell Activation through an Interaction with CARMA1 |
title | CKIP-1 Is an Intrinsic Negative Regulator of T-Cell Activation through an Interaction with CARMA1 |
title_full | CKIP-1 Is an Intrinsic Negative Regulator of T-Cell Activation through an Interaction with CARMA1 |
title_fullStr | CKIP-1 Is an Intrinsic Negative Regulator of T-Cell Activation through an Interaction with CARMA1 |
title_full_unstemmed | CKIP-1 Is an Intrinsic Negative Regulator of T-Cell Activation through an Interaction with CARMA1 |
title_short | CKIP-1 Is an Intrinsic Negative Regulator of T-Cell Activation through an Interaction with CARMA1 |
title_sort | ckip-1 is an intrinsic negative regulator of t-cell activation through an interaction with carma1 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894987/ https://www.ncbi.nlm.nih.gov/pubmed/24465689 http://dx.doi.org/10.1371/journal.pone.0085762 |
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