Nuclear Export of the NF-κB Inhibitor IκBα Is Required for Proper B Cell and Secondary Lymphoid Tissue Formation

Shelly M. Wuerzberger-Davis; Yuhong Chen; David T. Yang; Jeffrey D. Kearns; Paul W. Bates; Candace Lynch; Nicholas C. Ladell; Mei Yu; Andrew Podd; Hu Zeng; Tony T. Huang; Renren Wen; Alexander Hoffmann; Demin Wang; Shigeki Miyamoto

doi:10.1016/j.immuni.2011.01.014

Nuclear Export of the NF-κB Inhibitor IκBα Is Required for Proper B Cell and Secondary Lymphoid Tissue Formation

Shelly M. Wuerzberger-Davis, Yuhong Chen, David T. Yang, Jeffrey D. Kearns, Paul W. Bates, Candace Lynch, Nicholas C. Ladell, Mei Yu, Andrew Podd, Hu Zeng, Tony T. Huang, Renren Wen, Alexander Hoffmann, Demin Wang, Shigeki Miyamoto

Biology (Duluth)

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

27 Scopus citations

Abstract

The N-terminal nuclear export sequence (NES) of inhibitor of nuclear factor kappa B (NF-κB) alpha (IκBα) promotes NF-κB export from the cell nucleus to the cytoplasm, but the physiological role of this export regulation remains unknown. Here we report the derivation and analysis of genetically targeted mice harboring a germline mutation in IκBα NES. Mature B cells in the mutant mice displayed nuclear accumulation of inactive IκBα complexes containing a NF-κB family member, cRel, causing their spatial separation from the cytoplasmic IκB kinase. This resulted in severe reductions in constitutive and canonical NF-κB activities, synthesis of p100 and RelB NF-κB members, noncanonical NF-κB activity, NF-κB target gene induction, and proliferation and survival responses in B cells. Consequently, mice displayed defective B cell maturation, antibody production, and formation of secondary lymphoid organs and tissues. Thus, IκBα nuclear export is essential to maintain constitutive, canonical, and noncanonical NF-κB activation potentials in mature B cells in vivo.

Original language	English (US)
Pages (from-to)	188-200
Number of pages	13
Journal	Immunity
Volume	34
Issue number	2
DOIs	https://doi.org/10.1016/j.immuni.2011.01.014
State	Published - Feb 25 2011

Bibliographical note

Funding Information:
We thank A. Griep, P. Powers, C. Bartley, and M. Lye at the Transgenic Animal Facility at the University of Wisconsin Biotechnology Center for the gift of the TK-pflox8 targeting vector and assistance with the generation of the mutant mice, B. Seufzer for genotyping of the mice, and members of the S.M., D.W., and R.W. labs for stimulating discussions. This work was supported in part by National Institutes of Health grants R01 CA081065, R56 CA081065, CA077474, and R01 GM083681 (S.M.), T32 CA009614 (D.Y.), R01 AI083453 and P01 GM071862 (A.H.), R01 AI52327 (R.W.), and R01 HL073284, R01 AI079087, and P01 HL44612 (D.W.), by UWCCC Core grant P30 CA14520 (G. Wilding, PI), and by Scholar Award from the Leukemia & Lymphoma Society (D.W.).

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Wuerzberger-Davis, S. M., Chen, Y., Yang, D. T., Kearns, J. D., Bates, P. W., Lynch, C., Ladell, N. C., Yu, M., Podd, A., Zeng, H., Huang, T. T., Wen, R., Hoffmann, A., Wang, D., & Miyamoto, S. (2011). Nuclear Export of the NF-κB Inhibitor IκBα Is Required for Proper B Cell and Secondary Lymphoid Tissue Formation. Immunity, 34(2), 188-200. https://doi.org/10.1016/j.immuni.2011.01.014

Wuerzberger-Davis, SM, Chen, Y, Yang, DT, Kearns, JD, Bates, PW, Lynch, C, Ladell, NC, Yu, M, Podd, A, Zeng, H, Huang, TT, Wen, R, Hoffmann, A, Wang, D & Miyamoto, S 2011, 'Nuclear Export of the NF-κB Inhibitor IκBα Is Required for Proper B Cell and Secondary Lymphoid Tissue Formation', Immunity, vol. 34, no. 2, pp. 188-200. https://doi.org/10.1016/j.immuni.2011.01.014

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title = "Nuclear Export of the NF-κB Inhibitor IκBα Is Required for Proper B Cell and Secondary Lymphoid Tissue Formation",

abstract = "The N-terminal nuclear export sequence (NES) of inhibitor of nuclear factor kappa B (NF-κB) alpha (IκBα) promotes NF-κB export from the cell nucleus to the cytoplasm, but the physiological role of this export regulation remains unknown. Here we report the derivation and analysis of genetically targeted mice harboring a germline mutation in IκBα NES. Mature B cells in the mutant mice displayed nuclear accumulation of inactive IκBα complexes containing a NF-κB family member, cRel, causing their spatial separation from the cytoplasmic IκB kinase. This resulted in severe reductions in constitutive and canonical NF-κB activities, synthesis of p100 and RelB NF-κB members, noncanonical NF-κB activity, NF-κB target gene induction, and proliferation and survival responses in B cells. Consequently, mice displayed defective B cell maturation, antibody production, and formation of secondary lymphoid organs and tissues. Thus, IκBα nuclear export is essential to maintain constitutive, canonical, and noncanonical NF-κB activation potentials in mature B cells in vivo.",

author = "Wuerzberger-Davis, {Shelly M.} and Yuhong Chen and Yang, {David T.} and Kearns, {Jeffrey D.} and Bates, {Paul W.} and Candace Lynch and Ladell, {Nicholas C.} and Mei Yu and Andrew Podd and Hu Zeng and Huang, {Tony T.} and Renren Wen and Alexander Hoffmann and Demin Wang and Shigeki Miyamoto",

note = "Funding Information: We thank A. Griep, P. Powers, C. Bartley, and M. Lye at the Transgenic Animal Facility at the University of Wisconsin Biotechnology Center for the gift of the TK-pflox8 targeting vector and assistance with the generation of the mutant mice, B. Seufzer for genotyping of the mice, and members of the S.M., D.W., and R.W. labs for stimulating discussions. This work was supported in part by National Institutes of Health grants R01 CA081065, R56 CA081065, CA077474, and R01 GM083681 (S.M.), T32 CA009614 (D.Y.), R01 AI083453 and P01 GM071862 (A.H.), R01 AI52327 (R.W.), and R01 HL073284, R01 AI079087, and P01 HL44612 (D.W.), by UWCCC Core grant P30 CA14520 (G. Wilding, PI), and by Scholar Award from the Leukemia & Lymphoma Society (D.W.). ",

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AU - Wuerzberger-Davis, Shelly M.

AU - Chen, Yuhong

AU - Yang, David T.

AU - Kearns, Jeffrey D.

AU - Bates, Paul W.

AU - Lynch, Candace

AU - Ladell, Nicholas C.

AU - Yu, Mei

AU - Podd, Andrew

AU - Zeng, Hu

AU - Huang, Tony T.

AU - Wen, Renren

AU - Hoffmann, Alexander

AU - Wang, Demin

AU - Miyamoto, Shigeki

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PY - 2011/2/25

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N2 - The N-terminal nuclear export sequence (NES) of inhibitor of nuclear factor kappa B (NF-κB) alpha (IκBα) promotes NF-κB export from the cell nucleus to the cytoplasm, but the physiological role of this export regulation remains unknown. Here we report the derivation and analysis of genetically targeted mice harboring a germline mutation in IκBα NES. Mature B cells in the mutant mice displayed nuclear accumulation of inactive IκBα complexes containing a NF-κB family member, cRel, causing their spatial separation from the cytoplasmic IκB kinase. This resulted in severe reductions in constitutive and canonical NF-κB activities, synthesis of p100 and RelB NF-κB members, noncanonical NF-κB activity, NF-κB target gene induction, and proliferation and survival responses in B cells. Consequently, mice displayed defective B cell maturation, antibody production, and formation of secondary lymphoid organs and tissues. Thus, IκBα nuclear export is essential to maintain constitutive, canonical, and noncanonical NF-κB activation potentials in mature B cells in vivo.

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ER -

Nuclear Export of the NF-κB Inhibitor IκBα Is Required for Proper B Cell and Secondary Lymphoid Tissue Formation

Abstract

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