title: Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor-γ (PPARγ) are disrupted by retinal disease-associated mutations.
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, 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.
authors.affiliation: School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: Joel
authors.initials: J
authors.lastname: Fulton
authors.affiliation: School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: Bismoy
authors.initials: B
authors.lastname: Mazumder
authors.affiliation: School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Whitchurch
authors.affiliation: School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: Cintia J
authors.initials: CJ
authors.lastname: Monteiro
authors.affiliation: School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: Hilary M
authors.initials: HM
authors.lastname: Collins
authors.affiliation: School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: Chun M
authors.initials: CM
authors.lastname: Chan
authors.affiliation: School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Clemente
authors.affiliation: School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: Miguel
authors.initials: M
authors.lastname: Hernandez-Quiles
authors.affiliation: Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, UK.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Stewart
authors.affiliation: Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, UK.
authors.forename: Winfried M
authors.initials: WM
authors.lastname: Amoaku
authors.affiliation: School of Psychology, University of Nottingham, Nottingham, UK.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Moran
authors.affiliation: School of Veterinary Medicine and Science, University of Nottingham, Nottingham, UK.|Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Mongan
authors.affiliation: Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.|Department of Molecular Biology, Umeå University, Umeå, Sweden.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Persson
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Simak
authors.initials: S
authors.lastname: Ali
authors.affiliation: School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Heery
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D019281:Dimerization; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation / Q000235:genetics*; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics; D057093:Orphan Nuclear Receptors / Q000235:genetics*; D047495:PPAR gamma / Q000235:genetics*; D011487:Protein Conformation; D012160:Retina / Q000473:pathology*; D012164:Retinal Diseases / Q000235:genetics* / Q000473:pathology*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: C403073:NR2E3 protein, human; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors