title: Epigenetic regulation of Kcna3-encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4+ T-cell activation.
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.
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;
authors.forename: Jung-Ah
authors.initials: JA
authors.lastname: Kang
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;
authors.forename: Sang-Heon
authors.initials: SH
authors.lastname: Park
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;
authors.forename: Sang Phil
authors.initials: SP
authors.lastname: Jeong
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;
authors.forename: Min-Hee
authors.initials: MH
authors.lastname: Han
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;
authors.forename: Cho-Rong
authors.initials: CR
authors.lastname: Lee
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;
authors.forename: Kwang Min
authors.initials: KM
authors.lastname: Lee
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;
authors.forename: Namhee
authors.initials: N
authors.lastname: Kim
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;
authors.forename: Mi-Ryoung
authors.initials: MR
authors.lastname: Song
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea;
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.affiliation: School of Liberal Arts and Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;
authors.forename: Michael
authors.initials: M
authors.lastname: Ye
authors.affiliation: Department of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea;
authors.forename: Guhung
authors.initials: G
authors.lastname: Jung
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea;
authors.forename: Won-Woo
authors.initials: WW
authors.lastname: Lee
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Eom
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;
authors.forename: Chul-Seung
authors.initials: CS
authors.lastname: Park
authors.affiliation: 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.
authors.forename: Sung-Gyoo
authors.initials: SG
authors.lastname: Park
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling / Q000379:methods; D051664:Kv1.3 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011188:Potassium / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C549921:Crbn protein, mouse; D016207:Cytokines; D051664:Kv1.3 Potassium Channel; D009419:Nerve Tissue Proteins; D011188:Potassium; D002118:Calcium
keywords: CRBN; Kv1.3; T-cell activation; calcium flux; potassium flux