Impaired Vitamin D Signaling in T Cells From a Family With Hereditary Vitamin D Resistant Rickets
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Impaired Vitamin D Signaling in T Cells From a Family With Hereditary Vitamin D Resistant Rickets. / Al-Jaberi, Fatima A. H.; Kongsbak-Wismann, Martin; Aguayo-Orozco, Alejandro; Krogh, Nicolai; Buus, Terkild B.; Lopez, Daniel V.; Rode, Anna K. O.; Gravesen, Eva; Olgaard, Klaus; Brunak, Soren; Woetmann, Anders; odum, Niels; Bonefeld, Charlotte M.; Geisler, Carsten.
In: Frontiers in Immunology, Vol. 12, 684015, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Impaired Vitamin D Signaling in T Cells From a Family With Hereditary Vitamin D Resistant Rickets
AU - Al-Jaberi, Fatima A. H.
AU - Kongsbak-Wismann, Martin
AU - Aguayo-Orozco, Alejandro
AU - Krogh, Nicolai
AU - Buus, Terkild B.
AU - Lopez, Daniel V.
AU - Rode, Anna K. O.
AU - Gravesen, Eva
AU - Olgaard, Klaus
AU - Brunak, Soren
AU - Woetmann, Anders
AU - odum, Niels
AU - Bonefeld, Charlotte M.
AU - Geisler, Carsten
PY - 2021
Y1 - 2021
N2 - The active form of vitamin D, 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3), mediates its immunomodulatory effects by binding to the vitamin D receptor (VDR). Here, we describe a new point mutation in the DNA-binding domain of the VDR and its consequences for 1,25(OH)(2)D-3 signaling in T cells from heterozygous and homozygous carriers of the mutation. The mutation did not affect the overall structure or the ability of the VDR to bind 1,25(OH)(2)D-3 and the retinoid X receptor. However, the subcellular localization of the VDR was strongly affected and the transcriptional activity was abolished by the mutation. In heterozygous carriers of the mutation, 1,25(OH)(2)D-3-induced gene regulation was reduced by similar to 50% indicating that the expression level of wild-type VDR determines 1,25(OH)(2)D-3 responsiveness in T cells. We show that vitamin D-mediated suppression of vitamin A-induced gene regulation depends on an intact ability of the VDR to bind DNA. Furthermore, we demonstrate that vitamin A inhibits 1,25(OH)(2)D-3-induced translocation of the VDR to the nucleus and 1,25(OH)(2)D-3-induced up-regulation of CYP24A1. Taken together, this study unravels novel aspects of vitamin D signaling and function of the VDR in human T cells.
AB - The active form of vitamin D, 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3), mediates its immunomodulatory effects by binding to the vitamin D receptor (VDR). Here, we describe a new point mutation in the DNA-binding domain of the VDR and its consequences for 1,25(OH)(2)D-3 signaling in T cells from heterozygous and homozygous carriers of the mutation. The mutation did not affect the overall structure or the ability of the VDR to bind 1,25(OH)(2)D-3 and the retinoid X receptor. However, the subcellular localization of the VDR was strongly affected and the transcriptional activity was abolished by the mutation. In heterozygous carriers of the mutation, 1,25(OH)(2)D-3-induced gene regulation was reduced by similar to 50% indicating that the expression level of wild-type VDR determines 1,25(OH)(2)D-3 responsiveness in T cells. We show that vitamin D-mediated suppression of vitamin A-induced gene regulation depends on an intact ability of the VDR to bind DNA. Furthermore, we demonstrate that vitamin A inhibits 1,25(OH)(2)D-3-induced translocation of the VDR to the nucleus and 1,25(OH)(2)D-3-induced up-regulation of CYP24A1. Taken together, this study unravels novel aspects of vitamin D signaling and function of the VDR in human T cells.
KW - vitamin D
KW - vitamin D receptor
KW - HVDRR
KW - T cells
KW - vitamin A
KW - D-RECEPTOR
KW - DOWN-REGULATION
KW - ACID
U2 - 10.3389/fimmu.2021.684015
DO - 10.3389/fimmu.2021.684015
M3 - Journal article
C2 - 34093587
VL - 12
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
M1 - 684015
ER -
ID: 271688102