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Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor-γ (PPARγ) are disrupted by retinal disease-associated mutations

Fulton, Joel; Mazumder, Bismoy; Whitchurch, Jonathan B.; Monteiro, Cintia J.; Collins, Hilary M.; Chan, Chun M.; Clemente, Maria P.; Hernandez-Quiles, Miguel; Stewart, Elizabeth A. and Amoaku, Winfried M., et al. (2017) In Cell Death and Disease 8(3). p.2677-2677
Abstract

Photoreceptor-specific nuclear receptor (PNR/NR2E3) and Tailless homolog (TLX/NR2E1) are human orthologs of the NR2E group, a subgroup of phylogenetically related members of the nuclear receptor (NR) superfamily of transcription factors. We assessed the ability of these NRs to form heterodimers with other members of the human NRs representing all major subgroups. The TLX ligand-binding domain (LBD) did not appear to form homodimers or interact directly with any other NR tested. The PNR LBD was able to form homodimers, but also exhibited robust interactions with the LBDs of peroxisome proliferator-activated receptor-γ (PPARγ)/NR1C3 and thyroid hormone receptor b (TRb) TRβ/NR1A2. The binding of PNR to PPARγ was specific for this paralog,... (More)

Photoreceptor-specific nuclear receptor (PNR/NR2E3) and Tailless homolog (TLX/NR2E1) are human orthologs of the NR2E group, a subgroup of phylogenetically related members of the nuclear receptor (NR) superfamily of transcription factors. We assessed the ability of these NRs to form heterodimers with other members of the human NRs representing all major subgroups. The TLX ligand-binding domain (LBD) did not appear to form homodimers or interact directly with any other NR tested. The PNR LBD was able to form homodimers, but also exhibited robust interactions with the LBDs of peroxisome proliferator-activated receptor-γ (PPARγ)/NR1C3 and thyroid hormone receptor b (TRb) TRβ/NR1A2. The binding of PNR to PPARγ was specific for this paralog, as no interaction was observed with the LBDs of PPARα/NR1C1 or PPARδ/NR1C2. In support of these findings, PPARγ and PNR were found to be co-expressed in human retinal tissue extracts and could be co-immunoprecipitated as a native complex. Selected sequence variants in the PNR LBD associated with human retinopathies, or a mutation in the dimerization region of PPARγ LBD associated with familial partial lipodystrophy type 3, were found to disrupt PNR/PPARγ complex formation. Wild-type PNR, but not a PNR309G mutant, was able to repress PPARγ-mediated transcription in reporter assays. In summary, our results reveal novel heterodimer interactions in the NR superfamily, suggesting previously unknown functional interactions of PNR with PPARγ and TRβ that have potential importance in retinal development and disease.

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published
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Cell Death and Disease
volume
8
issue
3
pages
2677 - 2677
publisher
Nature Publishing Group
external identifiers
  • scopus:85032142385
  • wos:000397447100042
ISSN
2041-4889
DOI
10.1038/cddis.2017.98
language
English
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yes
id
158b6ceb-9590-4b5b-b8a8-4d7dd12d12f4
date added to LUP
2017-11-08 11:57:48
date last changed
2018-02-07 15:03:59
@article{158b6ceb-9590-4b5b-b8a8-4d7dd12d12f4,
  abstract     = {<p>Photoreceptor-specific nuclear receptor (PNR/NR2E3) and Tailless homolog (TLX/NR2E1) are human orthologs of the NR2E group, a subgroup of phylogenetically related members of the nuclear receptor (NR) superfamily of transcription factors. We assessed the ability of these NRs to form heterodimers with other members of the human NRs representing all major subgroups. The TLX ligand-binding domain (LBD) did not appear to form homodimers or interact directly with any other NR tested. The PNR LBD was able to form homodimers, but also exhibited robust interactions with the LBDs of peroxisome proliferator-activated receptor-γ (PPARγ)/NR1C3 and thyroid hormone receptor b (TRb) TRβ/NR1A2. The binding of PNR to PPARγ was specific for this paralog, as no interaction was observed with the LBDs of PPARα/NR1C1 or PPARδ/NR1C2. In support of these findings, PPARγ and PNR were found to be co-expressed in human retinal tissue extracts and could be co-immunoprecipitated as a native complex. Selected sequence variants in the PNR LBD associated with human retinopathies, or a mutation in the dimerization region of PPARγ LBD associated with familial partial lipodystrophy type 3, were found to disrupt PNR/PPARγ complex formation. Wild-type PNR, but not a PNR309G mutant, was able to repress PPARγ-mediated transcription in reporter assays. In summary, our results reveal novel heterodimer interactions in the NR superfamily, suggesting previously unknown functional interactions of PNR with PPARγ and TRβ that have potential importance in retinal development and disease.</p>},
  author       = {Fulton, Joel and Mazumder, Bismoy and Whitchurch, Jonathan B. and Monteiro, Cintia J. and Collins, Hilary M. and Chan, Chun M. and Clemente, Maria P. and Hernandez-Quiles, Miguel and Stewart, Elizabeth A. and Amoaku, Winfried M. and Moran, Paula M. and Mongan, Nigel P. and Persson, Jenny L. and Ali, Simak and Heery, David M},
  issn         = {2041-4889},
  language     = {eng},
  month        = {03},
  number       = {3},
  pages        = {2677--2677},
  publisher    = {Nature Publishing Group},
  series       = {Cell Death and Disease},
  title        = {Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor-γ (PPARγ) are disrupted by retinal disease-associated mutations},
  url          = {http://dx.doi.org/10.1038/cddis.2017.98},
  volume       = {8},
  year         = {2017},
}