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Sci Rep. 2015 Jun 1;5:10758. doi: 10.1038/srep10758.

Catalytic subunits of the phosphatase calcineurin interact with NF-κB-inducing kinase (NIK) and attenuate NIK-dependent gene expression.

Author information

1
Division of Cellular and Molecular Biology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
2
1] Division of Cellular and Molecular Biology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan [2] Department of Developmental and Regenerative Biology, Key Laboratory for Regenerative Medicine, Ministry of Education and International Base of Collaboration for Science and Technology, Ministry of Science and Technology, Jinan University, Guangzhou, China.
3
Division of Interactome Medical Sciences, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
4
1] Division of Interactome Medical Sciences, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan [2] Division of Molecular Biology, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki, Noda-shi, Chiba, Japan.
5
Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.

Abstract

Nuclear factor (NF)-κB-inducing kinase (NIK) is a serine/threonine kinase that activates NF-κB pathways, thereby regulating a wide variety of immune systems. Aberrant NIK activation causes tumor malignancy, suggesting a requirement for precise regulation of NIK activity. To explore novel interacting proteins of NIK, we performed in vitro virus screening and identified the catalytic subunit Aα isoform of serine/threonine phosphatase calcineurin (CnAα) as a novel NIK-interacting protein. The interaction of NIK with CnAα in living cells was confirmed by co-immunoprecipitation. Calcineurin catalytic subunit Aβ isoform (CnAβ) also bound to NIK. Experiments using domain deletion mutants suggested that CnAα and CnAβ interact with both the kinase domain and C-terminal region of NIK. Moreover, the phosphatase domain of CnAα is responsible for the interaction with NIK. Intriguingly, we found that TRAF3, a critical regulator of NIK activity, also binds to CnAα and CnAβ. Depletion of CnAα and CnAβ significantly enhanced lymphotoxin-β receptor (LtβR)-mediated expression of the NIK-dependent gene Spi-B and activation of RelA and RelB, suggesting that CnAα and CnAβ attenuate NF-κB activation mediated by LtβR-NIK signaling. Overall, these findings suggest a possible role of CnAα and CnAβ in modifying NIK functions.

PMID:
26029823
PMCID:
PMC5377069
DOI:
10.1038/srep10758
[Indexed for MEDLINE]
Free PMC Article

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