Query author contributions in Reactome
Reactome depends on collaboration between our curation team and outside experts to assemble and peer-review its pathway modules. The integration of ORCID within Reactome enables us to meet a key challenge with authoring, curating and reviewing biological information by incentivizing and crediting the external experts that contribute their expertise and time to the Reactome curation process. More information is available at ORCID and Reactome.
If you have an ORCID ID that is not listed on this page, please forward this information to us and we will update your Reactome pathway records.
Details on Person The vitamin D receptor (VDR) is a ligand-activated nuclear r...
| Class:Id | Summation:9795289 |
|---|---|
| _displayName | The vitamin D receptor (VDR) is a ligand-activated nuclear r... |
| _timestamp | 2022-08-04 04:36:40 |
| created | [InstanceEdit:9795295] Shamovsky, Veronica, 2022-08-04 |
| literatureReference | [LiteratureReference:9795283] Elevated NLRP3 Inflammasome Levels Correlate With Vitamin D in the Vitreous of Proliferative Diabetic Retinopathy [LiteratureReference:9795290] Vitamin D protects against high glucose-induced pancreatic β-cell dysfunction via AMPK-NLRP3 inflammasome pathway [LiteratureReference:9795266] Vitamin D3 Protects against Diabetic Retinopathy by Inhibiting High-Glucose-Induced Activation of the ROS/TXNIP/NLRP3 Inflammasome Pathway [LiteratureReference:9795338] EB1089 promotes the expression of vitamin D receptor in the intestinal epithelial cell line HT-29 and reduces lipopolysaccharide-induced inflammatory response [LiteratureReference:9795267] Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response [LiteratureReference:9795336] Vitamin D up-regulates the vitamin D receptor by protecting it from proteasomal degradation in human CD4+ T cells [LiteratureReference:9795332] Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression [LiteratureReference:9795293] Emerging Roles of Vitamin D-Induced Antimicrobial Peptides in Antiviral Innate Immunity [LiteratureReference:9795329] Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3 [LiteratureReference:9795276] Primary Vitamin D Target Genes of Human Monocytes [LiteratureReference:9795307] Vitamin D Receptor Inhibits NLRP3 Activation by Impeding Its BRCC3-Mediated Deubiquitination [LiteratureReference:9795321] STAT6/VDR Axis Mitigates Lung Inflammatory Injury by Promoting Nrf2 Signaling Pathway [LiteratureReference:9795323] Vitamin D receptor inhibits nuclear factor κB activation by interacting with IκB kinase β protein [LiteratureReference:9795316] The Non-Genomic Actions of Vitamin D |
| text | The vitamin D receptor (VDR) is a ligand-activated nuclear receptor which binds with high affinity the 1,25-dihydroxyvitamin D3 hormone (1,25(OH)2D3 or vitamin D3). VDR:1,25(OH)2D3 controls the expression of target genes that regulate calcium and phosphate plasma levels. Besides its function in calcium homeostasis, VDR:1,25(OH)2D3 axis has been implicated in regulation of immune responses (reviewed in Bishop EL et al. 2020; Ismailova A & White JH 2022; White JH 2022). Activated immune cells, such as macrophages, dendritic cells or T-cells, express VDR and 1α-hydroxylase (CYP27B1) that converts 25-hydroxyvitamin D to 1,25(OH)2D3 at sites of infection (Liu PT et al. 2006; Kongsbak M et al. 2014; Huang H et al. 2018). In immune cells, the ligand-bound VDR regulates the expression of genes encoding antimicrobial peptides (AMPs) and cytokines implicated in immune responses (Wang TT et al. 2004; Gombart AF et al. 2005; reviewed in Nurminen V et al. 2019; reviewed in White JH 2022). In addition to acting as a transcription factor, VDR modulates immune responses via targeting intracellular signaling events (reviewed in Hii CS & Ferrante A 2016; Bishop EL et al. 2020). Among these, the nuclear factor (NF)-kappa-B activity is inhibited upon direct interaction of ligand-bound VDR with I-κB kinase β (IKKβ or IKBKB), the upstream regulator of the NF-kappa-B pathway (Chen Y et al. 2013). Further, VDR:1,25(OH)2D3 also protects cells through inhibiting ROS production (Lu L et al. 2018; Yang Y et al. 2022). Both NF-kapp-B signaling pathway and elevated ROS production contribute to the activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. VDR can directly interact with NLRP3 (Huang H et al. 2018; Rao Z et al. 2019). In ex vivo mouse CD4+ T cells, VDR co-immunoprecipitated with NLRP3 in nuclear extracts (Huang H et al. 2018). The NLRP3:VDR complex fromation was also detected upon co-expression of tagged proteins in human embryonic kidney (HEK)293T cells (Huang H et al. 2018; Rao Z et al. 2019). Endogenous immunoassay using lipopolysaccharide (LPS)-primed mouse macrophages further confirmed the NLRP3:VDR interaction (Rao Z et al. 2019). Mutagenesis analysis revealed that the ligand binding domain (LBD) of VDR was required for this interaction. Pretreatment with EB1089, a VDR agonist, inhibited inflammatory responses via promoting the VDR expression and reducing expression levels of caspase-1, NLRP3, TLR4, MyD88, and NF-kappa-B in LPS-treated human colorectal adenocarcinoma cells HT-29 with epithelial morphology (Lu D et al. 2022). In LPS-primed mouse macrophages, VDR inhibited caspase-1 activation, IL-1β secretion and ASC speck formation (Rao Z et al. 2019). VDR also attenuated the binding of BRCC3 to NLRP3 and inhibited deubiquitination of NLRP3 upon co-expression of tagged proteins in HEK293T cells (Rao Z et al. 2019). These data suggest that VDR binds NLRP3 disrupting NLRP3:BRCC3 complex formation thereby preventing BRCC3-mediated deubiquitination and activation of NLRP3. Deficiency of vitamin D or VDR and/or inappropriate NLRP3-inflammasome activation has been linked to a wide range of human disorders that involve chronic inflammation, including autoimmune diseases, metabolic disorders, cancer, and high susceptibility to infections. For example, increased NLRP3 inflammasome activity correlated with decreased vitamin D3 concentrations in the vitreous of patients with proliferative diabetic retinopathy (PDR) which may be linked to PDR pathogenesis (Lu L et al. 2021). Further, VDR deficiency enhanced NLRP3-mediated inflammation in mouse models of LPS-induced sepsis and alum-induced peritonitis (Rao Z et al. 2019). In diabetic rats, vitamin D3 significantly downregulated intracellular ROS and inhibited TRX-interacting protein (TXNIP)-NLRP3 inflammasome pathway activation (Lu L et al. 2018). Vitamin D3 showed protective effect in high-glucose-induced rat model of impaired glucose tolerance by enhancing the AMPK pathway, thus inhibiting the mTOR pathway and inhibiting NLRP3 inflammasome activation in β-cell (Wu M et al. 2022). This Reactome event shows binding of VDR:1,25(OH)2D3 to NLRP3. |
| (summation) | [Reaction:9795312] NLRP3 binds 1,25(OH)2D:VDR [Homo sapiens] |
| [Change default viewing format] | |
No pathways have been reviewed or authored by The vitamin D receptor (VDR) is a ligand-activated nuclear r... (9795289)
