Zebrafish IκB kinase 1 negatively regulates NF-κB activity

Ricardo G. Correa; Takaaki Matsui; Vinay Tergaonkar; Concepcion Rodriguez-Esteban; Juan Carlos Izpisua-Belmonte; Inder M. Verma

doi:10.1016/j.cub.2005.06.023

Zebrafish IκB kinase 1 negatively regulates NF-κB activity

Ricardo G. Correa, Takaaki Matsui, Vinay Tergaonkar, Concepcion Rodriguez-Esteban, Juan Carlos Izpisua-Belmonte, Inder M. Verma^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

75 Scopus citations

Abstract

The IκB kinase (IKK) activity is critical for processing IκB inhibitory proteins and activating the NF-κB signaling, which is involved in a series of physiological and developmental steps in vertebrates [1-4]. The IKK activity resides in two catalytic subunits, IKK1 and IKK2, and two regulatory subunits, NEMO and ELKS [5-8]. IKK2 is the major cytokine-responsive IκB kinase [9-11] because depletion of IKK1 does not interfere with the IKK activity [12-14]. In fact, IKK1^-/- mice display morphological abnormalities that are independent of its kinase activity and NF-κB activation [12-14]. Hence, using zebrafish (Danio rerio) as a model, we examined the evolutionary role of IKK1 in modulating NF-κB. Ikk1^-/- zebrafish embryos present head and tail malformations and, surprisingly, show upregulation of NF-κB-responsive genes and increased NF-κB-dependent apoptosis. Overexpression of ikk1 leads to midline structure defects that resemble NF-κB blockage in vivo [1]. Zebrafish Ikk1 forms complexes with NEMO that represses NF-κB in vertebrate cells. Indeed, truncation of its NEMO binding domain (NBD) restores NF-κB-dependent transcriptional activity and, consequently, the ikk1-overexpressing phenotype. Here, we report that Ikk1 negatively regulates NF-κB by sequestering NEMO from active IKK complexes, indicating that IKK1 can function as a repressor of NF-κB.

Original language	English (US)
Pages (from-to)	1291-1295
Number of pages	5
Journal	Current Biology
Volume	15
Issue number	14
DOIs	https://doi.org/10.1016/j.cub.2005.06.023
State	Published - Jul 26 2005
Externally published	Yes

Bibliographical note

Funding Information:
We thank Q. Li, Y. Kawakami, and C. Callol-Massot for their experimental assistance. We also thank C.D. Stern, V. Bottero, R. Sousa-Neves, and C.M. Mizutani for comments on the manuscript. R.G.C. is supported by a training grant from the National Institutes of Health (NIH). T.M. is supported by a JSPS postdoctoral fellowship for Research Abroad, Japan. V.T. is supported by a grant from the Leukemia and Lymphoma Society. The J.C.I.B. laboratory is supported by grants from the March of Dimes, HSPO, and the G. Harold and Leila Y. Mathers Charitable Foundation. I.M.V. is an American Cancer Society Professor of Molecular Biology and supported in part by grants from the NIH; the Larry L. Hillblom Foundation, Inc.; the Lebensfeld Foundation; the Wayne and Gladys Valley Foundation; and the H.N. and Frances C. Berger Foundation.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
General Agricultural and Biological Sciences

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title = "Zebrafish IκB kinase 1 negatively regulates NF-κB activity",

abstract = "The IκB kinase (IKK) activity is critical for processing IκB inhibitory proteins and activating the NF-κB signaling, which is involved in a series of physiological and developmental steps in vertebrates [1-4]. The IKK activity resides in two catalytic subunits, IKK1 and IKK2, and two regulatory subunits, NEMO and ELKS [5-8]. IKK2 is the major cytokine-responsive IκB kinase [9-11] because depletion of IKK1 does not interfere with the IKK activity [12-14]. In fact, IKK1-/- mice display morphological abnormalities that are independent of its kinase activity and NF-κB activation [12-14]. Hence, using zebrafish (Danio rerio) as a model, we examined the evolutionary role of IKK1 in modulating NF-κB. Ikk1-/- zebrafish embryos present head and tail malformations and, surprisingly, show upregulation of NF-κB-responsive genes and increased NF-κB-dependent apoptosis. Overexpression of ikk1 leads to midline structure defects that resemble NF-κB blockage in vivo [1]. Zebrafish Ikk1 forms complexes with NEMO that represses NF-κB in vertebrate cells. Indeed, truncation of its NEMO binding domain (NBD) restores NF-κB-dependent transcriptional activity and, consequently, the ikk1-overexpressing phenotype. Here, we report that Ikk1 negatively regulates NF-κB by sequestering NEMO from active IKK complexes, indicating that IKK1 can function as a repressor of NF-κB.",

author = "Correa, {Ricardo G.} and Takaaki Matsui and Vinay Tergaonkar and Concepcion Rodriguez-Esteban and Izpisua-Belmonte, {Juan Carlos} and Verma, {Inder M.}",

note = "Funding Information: We thank Q. Li, Y. Kawakami, and C. Callol-Massot for their experimental assistance. We also thank C.D. Stern, V. Bottero, R. Sousa-Neves, and C.M. Mizutani for comments on the manuscript. R.G.C. is supported by a training grant from the National Institutes of Health (NIH). T.M. is supported by a JSPS postdoctoral fellowship for Research Abroad, Japan. V.T. is supported by a grant from the Leukemia and Lymphoma Society. The J.C.I.B. laboratory is supported by grants from the March of Dimes, HSPO, and the G. Harold and Leila Y. Mathers Charitable Foundation. I.M.V. is an American Cancer Society Professor of Molecular Biology and supported in part by grants from the NIH; the Larry L. Hillblom Foundation, Inc.; the Lebensfeld Foundation; the Wayne and Gladys Valley Foundation; and the H.N. and Frances C. Berger Foundation. ",

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AU - Correa, Ricardo G.

AU - Matsui, Takaaki

AU - Tergaonkar, Vinay

AU - Rodriguez-Esteban, Concepcion

AU - Izpisua-Belmonte, Juan Carlos

AU - Verma, Inder M.

N1 - Funding Information: We thank Q. Li, Y. Kawakami, and C. Callol-Massot for their experimental assistance. We also thank C.D. Stern, V. Bottero, R. Sousa-Neves, and C.M. Mizutani for comments on the manuscript. R.G.C. is supported by a training grant from the National Institutes of Health (NIH). T.M. is supported by a JSPS postdoctoral fellowship for Research Abroad, Japan. V.T. is supported by a grant from the Leukemia and Lymphoma Society. The J.C.I.B. laboratory is supported by grants from the March of Dimes, HSPO, and the G. Harold and Leila Y. Mathers Charitable Foundation. I.M.V. is an American Cancer Society Professor of Molecular Biology and supported in part by grants from the NIH; the Larry L. Hillblom Foundation, Inc.; the Lebensfeld Foundation; the Wayne and Gladys Valley Foundation; and the H.N. and Frances C. Berger Foundation.

PY - 2005/7/26

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N2 - The IκB kinase (IKK) activity is critical for processing IκB inhibitory proteins and activating the NF-κB signaling, which is involved in a series of physiological and developmental steps in vertebrates [1-4]. The IKK activity resides in two catalytic subunits, IKK1 and IKK2, and two regulatory subunits, NEMO and ELKS [5-8]. IKK2 is the major cytokine-responsive IκB kinase [9-11] because depletion of IKK1 does not interfere with the IKK activity [12-14]. In fact, IKK1-/- mice display morphological abnormalities that are independent of its kinase activity and NF-κB activation [12-14]. Hence, using zebrafish (Danio rerio) as a model, we examined the evolutionary role of IKK1 in modulating NF-κB. Ikk1-/- zebrafish embryos present head and tail malformations and, surprisingly, show upregulation of NF-κB-responsive genes and increased NF-κB-dependent apoptosis. Overexpression of ikk1 leads to midline structure defects that resemble NF-κB blockage in vivo [1]. Zebrafish Ikk1 forms complexes with NEMO that represses NF-κB in vertebrate cells. Indeed, truncation of its NEMO binding domain (NBD) restores NF-κB-dependent transcriptional activity and, consequently, the ikk1-overexpressing phenotype. Here, we report that Ikk1 negatively regulates NF-κB by sequestering NEMO from active IKK complexes, indicating that IKK1 can function as a repressor of NF-κB.

AB - The IκB kinase (IKK) activity is critical for processing IκB inhibitory proteins and activating the NF-κB signaling, which is involved in a series of physiological and developmental steps in vertebrates [1-4]. The IKK activity resides in two catalytic subunits, IKK1 and IKK2, and two regulatory subunits, NEMO and ELKS [5-8]. IKK2 is the major cytokine-responsive IκB kinase [9-11] because depletion of IKK1 does not interfere with the IKK activity [12-14]. In fact, IKK1-/- mice display morphological abnormalities that are independent of its kinase activity and NF-κB activation [12-14]. Hence, using zebrafish (Danio rerio) as a model, we examined the evolutionary role of IKK1 in modulating NF-κB. Ikk1-/- zebrafish embryos present head and tail malformations and, surprisingly, show upregulation of NF-κB-responsive genes and increased NF-κB-dependent apoptosis. Overexpression of ikk1 leads to midline structure defects that resemble NF-κB blockage in vivo [1]. Zebrafish Ikk1 forms complexes with NEMO that represses NF-κB in vertebrate cells. Indeed, truncation of its NEMO binding domain (NBD) restores NF-κB-dependent transcriptional activity and, consequently, the ikk1-overexpressing phenotype. Here, we report that Ikk1 negatively regulates NF-κB by sequestering NEMO from active IKK complexes, indicating that IKK1 can function as a repressor of NF-κB.

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Zebrafish IκB kinase 1 negatively regulates NF-κB activity

Abstract

Bibliographical note

ASJC Scopus subject areas

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