Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):8771-6. doi: 10.1073/pnas.1502166113. Epub 2016 Jul 20.

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

Author information

1
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;
2
Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea;
3
School of Liberal Arts and Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;
4
Department of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea;
5
Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea;
6
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea; Cell Logistics Research Center, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea sgpark@gist.ac.kr.

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.

KEYWORDS:

CRBN; Kv1.3; T-cell activation; calcium flux; potassium flux

PMID:
27439875
PMCID:
PMC4978309
DOI:
10.1073/pnas.1502166113
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center