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Epigenetic regulation of Kcna3-encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4+ T-cell activation.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2016 Aug 02; Vol. 113 (31), pp. 8771-6. Date of Electronic Publication: 2016 Jul 20. - Publication Year :
- 2016
-
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.
- Subjects :
- Adaptor Proteins, Signal Transducing
Animals
CD4-Positive T-Lymphocytes cytology
Calcium metabolism
Cells, Cultured
Cytokines metabolism
Encephalomyelitis, Autoimmune, Experimental genetics
Encephalomyelitis, Autoimmune, Experimental metabolism
Gene Expression Profiling methods
Kv1.3 Potassium Channel metabolism
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Nerve Tissue Proteins metabolism
Potassium metabolism
CD4-Positive T-Lymphocytes metabolism
Epigenesis, Genetic
Kv1.3 Potassium Channel genetics
Lymphocyte Activation genetics
Nerve Tissue Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 113
- Issue :
- 31
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 27439875
- Full Text :
- https://doi.org/10.1073/pnas.1502166113