In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 31 ( 2016-08-02), p. 8771-8776
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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1502166113
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2016
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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