Tissue Development, Repair, and Remodeling - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 717

Adopted orphan nuclear receptors are receptors for which ligands have been
identified afterward. Nuclear receptors for retinoic acid, fatty acid metabolites, and
oxysterols, form a third family.
Nuclear receptors for non-steroids, such as peroxisome proliferator-activated
(NR1c1-NR1c3) and liver X (NR1h2-NR1h3) receptors usually build heterodimers
with retinoid X receptors (NR2b1-NR2b3) and bind constitutively to their specific
hormone response elements, liganded or not. Both PPAR-RXR and LXR-RXR
heterodimers act as transcriptional repressors in the absence of ligand. They actually
interact with corepressor complexes.
Nuclear receptors impede pro-inflammatory programs of gene expression in
macrophages, microglial cells [ 1463 ]. They indeed operate in the turnover or
recruitment of corepressors and coactivators of gene expression. Transrepression
refers to indirect tethering of nuclear receptors with target genes rather than direct,
sequence-specific DNA connection.
The nuclear receptor corepressors NCoR1 44 and NCoR2 45 complex to maintain
a basal repression of a subset of genes activated by Toll-like receptors and other
pro-inflammatory pathways [ 1463 ].
The NCoR corepressor complex interact with transcriptional repressors, such
as C-promoter binding factor CBF1, 46 myoblast determination protein (MyoD),
and signal transducer and activator of transcription STAT5 [ 1463 ]. 47

The NCoR

corepressor complex must be cleared for gene activation. 48
Peroxisome proliferator-activated receptor PPAR

(NR1c3) and liver X receptors
prevent the removal of NCoR1-NCoR2 complexes in response to inflammatory
signals [ 1463 ]. Liganded PPAR

γ

attaches to small ubiquitin-related modifier
SUMo1 using Ub conjugase UbC9 and SUMo ligase protein inhibitor of activated
STAT PIAS1 [ 1463 ]. Sumoylated PPAR

γ

targets the NCoR complex and prevents
its ubiquitination that leads to NCoR clearance from gene promoters. In addition,
liganded LXR

γ

(NR1h3 and NR1h2) are sumoylated with SUMo2
or SUMo3 using UbC9 and HDAC4 histone deacetylase. Sumoylated LXRs also

α and LXR β

44 A.k.a. T 3 receptor-associating cofactor or thyroid hormone and retinoic acid receptor-associated
corepressor TRAC1.
45 A.k.a. silencing mediator of retinoic acid and thyroid hormone receptor [SMRT] as well as
thyroid hormone and retinoic acid receptor-associated corepressor TRAC1 (!).
46 A.k.a. recombination signal-binding protein for immunoglobulin-

J region (RBPJ).
47 Nuclear receptor corepressor NCoR1 can be recruited to inflammatory response genes by non-
phosphorylated Jun and NCoR2 by translocated ETS leukemia repressor (TEL) and P50 subunit
of NF

κ

κ κ

B. Factor Jun can be phosphorylated by IKK to liberate the promoters of NF B-binding

genes.
48 Components of the NCoR-HDAC3 complex transducin- β -like protein TBL1 (X-linked
[TBL1X] or Y-linked [TBL1Y]) and/or TBL1-related protein TBLR1 (in fact, TBL1XR1)
operate as adaptors that, once phosphorylated by activator kinases such as calmodulin-dependent
protein kinase CamK2, mediate the recruitment of the ubiquitin conjugase homolog UbCH5 that
ubiquitinates the NCoR1-HDAC3 and/or NCoR2-HDAC3 complexes for removal from gene
promoters by the 19S proteasome subunit.