Review
NR4A nuclear receptors are orphans but not lonesome

https://doi.org/10.1016/j.bbamcr.2014.06.010Get rights and content
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Highlights

  • Nuclear receptors Nur77, Nurr1 and NOR-1 are ‘orphan’ receptors of the NR4A subfamily.

  • The NR4A receptors have no ligands.

  • The known protein–protein interactions of all three NR4A receptors are summarized.

  • Interacting proteins are transcription factors, coregulators or protein kinases.

  • Protein–protein interactions modulate NR4A receptor activity and function.

Abstract

The NR4A subfamily of nuclear receptors consists of three mammalian members: Nur77, Nurr1, and NOR-1. The NR4A receptors are involved in essential physiological processes such as adaptive and innate immune cell differentiation, metabolism and brain function. They act as transcription factors that directly modulate gene expression, but can also form trans-repressive complexes with other transcription factors. In contrast to steroid hormone nuclear receptors such as the estrogen receptor or the glucocorticoid receptor, no ligands have been described for the NR4A receptors. This lack of known ligands might be explained by the structure of the ligand-binding domain of NR4A receptors, which shows an active conformation and a ligand-binding pocket that is filled with bulky amino acid side-chains. Other mechanisms, such as transcriptional control, post-translational modifications and protein–protein interactions therefore seem to be more important in regulating the activity of the NR4A receptors. For Nur77, over 80 interacting proteins (the interactome) have been identified so far, and roughly half of these interactions has been studied in more detail. Although the NR4As show some overlap in interacting proteins, less information is available on the interactome of Nurr1 and NOR-1. Therefore, the present review will describe the current knowledge on the interactomes of all three NR4A nuclear receptors with emphasis on Nur77.

Abbreviations

6-MP
6-mercaptopurine
9-cis-RA
9-cis-retinoic acid
AMP
adenosine monophosphate
AMPK
AMP-activated protein kinase
Cam-kinase
calcium/calmodulin-dependent protein kinase
CREB
cAMP response element binding protein
DBD
DNA-binding domain
DSB
DNA double-strand break
E2
17-β-estradiol
HAT
histone acetyltransferase
HDAC
histone deacetylase
HIF-1α
hypoxia inducible factor-1α
HPA
hypothalamo-pituitary-adrenal
LBD
ligand-binding domain
LXRs
liver X receptors
MDM2
mouse double minute 2
NBRE
NGFI-B response element
NES
nuclear export sequence
N-term
amino-terminal domain
NurRE
Nur-response elements
PI3K
phosphatidylinositol 3-kinase
PIP3
phosphatidylinositol(3,4,5)phosphate
PKC
protein kinase C
POMC
pro-opiomelanocortin
PPARs
peroxisome proliferator-activated receptors
βRARE
RA-response element of the RARβ promoter
RXRs
retinoid X receptors
StAR
steroidogenic acute regulatory protein
Treg
regulatory T cells

Keywords

Nuclear receptor
Protein–protein interaction
Nur77
Nurr1
NOR-1
NR4A

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1

These authors contributed equally.