Epigenetic regulation of Kcna3-encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4+ T-cell activation

Jung Ah Kang, Sang Heon Park, Sang Phil Jeong, Min Hee Han, Cho Rong Lee, Kwang Min Lee, Namhee Kim, Mi Ryoung Song, Murim Choi, Michael Ye, Guhung Jung, Won Woo Leee, Soo Hyun Eom, Chul Seung Park, Sung Gyoo Park

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The role of cereblon (CRBN) in T cells is not well understood. We generated mice with a deletion in Crbn and found cereblon to be an important antagonist of T-cell activation. In mice lacking CRBN, CD4+ T cells show increased activation and IL-2 production on T-cell receptor stimulation, ultimately resulting in increased potassium flux and calcium-mediated signaling. CRBN restricts T-cell activation via epigenetic modification of Kcna3, which encodes the Kv1.3 potassium channel required for robust calcium influx in T cells. CRBN binds directly to conserved DNA elements adjacent to Kcna3 via a previously uncharacterized DNA-binding motif. Consequently, in the absence of CRBN, the expression of Kv1.3 is derepressed, resulting in increased Kv1.3 expression, potassium flux, and CD4+ T-cell hyperactivation. In addition, experimental autoimmune encephalomyelitis in T-cell-specific Crbn-deficient mice was exacerbated by increased T-cell activation via Kv1.3. Thus, CRBN limits CD4+ T-cell activation via epigenetic regulation of Kv1.3 expression.

Original languageEnglish
Pages (from-to)8771-8776
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number31
DOIs
StatePublished - 2 Aug 2016

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Kv1.3 Potassium Channel
Epigenomics
T-Lymphocytes
Potassium
Nucleotide Motifs
Calcium Signaling
Autoimmune Experimental Encephalomyelitis
T-Cell Antigen Receptor
Interleukin-2

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Kang, Jung Ah ; Park, Sang Heon ; Jeong, Sang Phil ; Han, Min Hee ; Lee, Cho Rong ; Lee, Kwang Min ; Kim, Namhee ; Song, Mi Ryoung ; Choi, Murim ; Ye, Michael ; Jung, Guhung ; Leee, Won Woo ; Eom, Soo Hyun ; Park, Chul Seung ; Park, Sung Gyoo. / Epigenetic regulation of Kcna3-encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4+ T-cell activation. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 31. pp. 8771-8776.
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title = "Epigenetic regulation of Kcna3-encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4+ T-cell activation",
abstract = "The role of cereblon (CRBN) in T cells is not well understood. We generated mice with a deletion in Crbn and found cereblon to be an important antagonist of T-cell activation. In mice lacking CRBN, CD4+ T cells show increased activation and IL-2 production on T-cell receptor stimulation, ultimately resulting in increased potassium flux and calcium-mediated signaling. CRBN restricts T-cell activation via epigenetic modification of Kcna3, which encodes the Kv1.3 potassium channel required for robust calcium influx in T cells. CRBN binds directly to conserved DNA elements adjacent to Kcna3 via a previously uncharacterized DNA-binding motif. Consequently, in the absence of CRBN, the expression of Kv1.3 is derepressed, resulting in increased Kv1.3 expression, potassium flux, and CD4+ T-cell hyperactivation. In addition, experimental autoimmune encephalomyelitis in T-cell-specific Crbn-deficient mice was exacerbated by increased T-cell activation via Kv1.3. Thus, CRBN limits CD4+ T-cell activation via epigenetic regulation of Kv1.3 expression.",
author = "Kang, {Jung Ah} and Park, {Sang Heon} and Jeong, {Sang Phil} and Han, {Min Hee} and Lee, {Cho Rong} and Lee, {Kwang Min} and Namhee Kim and Song, {Mi Ryoung} and Murim Choi and Michael Ye and Guhung Jung and Leee, {Won Woo} and Eom, {Soo Hyun} and Park, {Chul Seung} and Park, {Sung Gyoo}",
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Kang, JA, Park, SH, Jeong, SP, Han, MH, Lee, CR, Lee, KM, Kim, N, Song, MR, Choi, M, Ye, M, Jung, G, Leee, WW, Eom, SH, Park, CS & Park, SG 2016, 'Epigenetic regulation of Kcna3-encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4+ T-cell activation', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 31, pp. 8771-8776. https://doi.org/10.1073/pnas.1502166113

Epigenetic regulation of Kcna3-encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4+ T-cell activation. / Kang, Jung Ah; Park, Sang Heon; Jeong, Sang Phil; Han, Min Hee; Lee, Cho Rong; Lee, Kwang Min; Kim, Namhee; Song, Mi Ryoung; Choi, Murim; Ye, Michael; Jung, Guhung; Leee, Won Woo; Eom, Soo Hyun; Park, Chul Seung; Park, Sung Gyoo.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 31, 02.08.2016, p. 8771-8776.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Epigenetic regulation of Kcna3-encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4+ T-cell activation

AU - Kang, Jung Ah

AU - Park, Sang Heon

AU - Jeong, Sang Phil

AU - Han, Min Hee

AU - Lee, Cho Rong

AU - Lee, Kwang Min

AU - Kim, Namhee

AU - Song, Mi Ryoung

AU - Choi, Murim

AU - Ye, Michael

AU - Jung, Guhung

AU - Leee, Won Woo

AU - Eom, Soo Hyun

AU - Park, Chul Seung

AU - Park, Sung Gyoo

PY - 2016/8/2

Y1 - 2016/8/2

N2 - The role of cereblon (CRBN) in T cells is not well understood. We generated mice with a deletion in Crbn and found cereblon to be an important antagonist of T-cell activation. In mice lacking CRBN, CD4+ T cells show increased activation and IL-2 production on T-cell receptor stimulation, ultimately resulting in increased potassium flux and calcium-mediated signaling. CRBN restricts T-cell activation via epigenetic modification of Kcna3, which encodes the Kv1.3 potassium channel required for robust calcium influx in T cells. CRBN binds directly to conserved DNA elements adjacent to Kcna3 via a previously uncharacterized DNA-binding motif. Consequently, in the absence of CRBN, the expression of Kv1.3 is derepressed, resulting in increased Kv1.3 expression, potassium flux, and CD4+ T-cell hyperactivation. In addition, experimental autoimmune encephalomyelitis in T-cell-specific Crbn-deficient mice was exacerbated by increased T-cell activation via Kv1.3. Thus, CRBN limits CD4+ T-cell activation via epigenetic regulation of Kv1.3 expression.

AB - The role of cereblon (CRBN) in T cells is not well understood. We generated mice with a deletion in Crbn and found cereblon to be an important antagonist of T-cell activation. In mice lacking CRBN, CD4+ T cells show increased activation and IL-2 production on T-cell receptor stimulation, ultimately resulting in increased potassium flux and calcium-mediated signaling. CRBN restricts T-cell activation via epigenetic modification of Kcna3, which encodes the Kv1.3 potassium channel required for robust calcium influx in T cells. CRBN binds directly to conserved DNA elements adjacent to Kcna3 via a previously uncharacterized DNA-binding motif. Consequently, in the absence of CRBN, the expression of Kv1.3 is derepressed, resulting in increased Kv1.3 expression, potassium flux, and CD4+ T-cell hyperactivation. In addition, experimental autoimmune encephalomyelitis in T-cell-specific Crbn-deficient mice was exacerbated by increased T-cell activation via Kv1.3. Thus, CRBN limits CD4+ T-cell activation via epigenetic regulation of Kv1.3 expression.

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U2 - 10.1073/pnas.1502166113

DO - 10.1073/pnas.1502166113

M3 - Article

C2 - 27439875

AN - SCOPUS:84982736723

VL - 113

SP - 8771

EP - 8776

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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