Nuclear receptors (Transcription factors)

Key features:
Nuclear Receptors (Transcription Factors) have the ability to directly bind to DNA (= DNA-binding proteins) and regulate the expression of adjacent genes; they are intracellular receptors in contrast to membrane-bound receptors

Shown is the dimer of an intracellular receptor with an amino terminus (green), DNA binding domain (DNA-B.) and carboxyl terminus (LBD L).There are three important domains within the transcription factor: the DNA binding domain (DNA-B), the transactivation domain and the ligand binding domain (LBD L).

After interaction with a ligand, two receptor proteins can associate to form a holoprotein via the dimerization domain, thereby the holoprotein to DNA recognition sequences can bind.

Nuclear Receptors (Transcription Factors) occur in the cytoplasm (e.g., Glucocorticoid receptor (GR)) or in the cell nucleus (e.g., Thyroid hormone receptor). In the cytoplasm, heat shock proteins (HSPs) are responsible for the correct folding of the receptor proteins (1).

Signal transduction at nuclear receptors (transcription factors):
Two proteins of a receptor (e.g., hormone receptor) in the cytoplasm are shown at the top left. Two chaperones, HSP-90, stabilize the folding of the two proteins. A ligand enters the cytoplasm and binds to the receptor proteins. These dimerize, and the HSP-90 molecules dissociate. The receptor-ligand complex translocates into the cell nucleus, where it binds to DNA recognition sequences. Transcription is triggered. If another transcription factor is activated via another (membrane-based) receptor, it can either bind to the ligand-receptor complex and prevent transcription, or itself binds to DNA and trigger transcription.

Bile Acids / Bile Salts are endogenous ligands for Nuclear Receptors (Transcription Factors). Nuclear Receptors (Transcription Factors) Activate Mechanisms that Lower the Abundance of Ligands that Activate Them (negative feedback loop) (2).

They have been shown to regulate the essential aspect of innate immunity and production of OPN in several experimental settings, but this information lacks for FXR (3, 4, 5, 6, 7, 8).

References:

(1) Geisslinger et al. 2020 Wissenschaftliche Verlagsgesellschaft mbH ISBN 978-3-8047-3663-4
(2) Schubert et al. 2017 Immunological Reviews 279: 23-35
(3) Glass et al. 2000 Genes Dev. 14: 121-141
(4) Oyama et al. 2002 Circ. Res. 90: 348-355
(5) Castrillo & Tontonoz 2004 Annu. Rev. Cell Dev. Biol. 20: 455-480
(6) Ogawa et al. 2005 Circ. Res. 95: 59-67
(7) Glass et al. 2006 Nat. Rev. Immunol. 6: 44-55
(8) Nakamachi et al. 2007 Diabetes 56: 1662-1670