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

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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

Bibliographical note

Funding Information:
National Research Foundation of Korea (Grants NRF-2013R1A1A2010995 and NRF-2016R1A5A1007318

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