1. Epigenetic regulation of Kcna3-encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4+ T-cell activation.
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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 Lee, Soo Hyun Eom, Chul-Seung Park, and Sung-Gyoo Park
- Subjects
T cells ,EPIGENETICS ,POTASSIUM channels ,CALCIUM channels ,DNA-binding proteins - 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. [ABSTRACT FROM AUTHOR]- Published
- 2016
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