scholarly journals Nuclear Receptors as Autophagy-Based Antimicrobial Therapeutics

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1979
Author(s):  
Prashanta Silwal ◽  
Seungwha Paik ◽  
Sang Min Jeon ◽  
Eun-Kyeong Jo
Keyword(s):  
Retinoic Acid ◽  
Nuclear Receptors ◽  
Hormone Receptors ◽  
Emerging Infectious Diseases ◽  
Peroxisome Proliferator ◽  
Vitamin D Receptors ◽  
Gene Sets ◽  
Intracellular Process ◽  
Peroxisome Proliferator Activated Receptors ◽  
X Receptors

Autophagy is an intracellular process that targets intracellular pathogens for lysosomal degradation. Autophagy is tightly controlled at transcriptional and post-translational levels. Nuclear receptors (NRs) are a family of transcriptional factors that regulate the expression of gene sets involved in, for example, metabolic and immune homeostasis. Several NRs show promise as host-directed anti-infectives through the modulation of autophagy activities by their natural ligands or small molecules (agonists/antagonists). Here, we review the roles and mechanisms of NRs (vitamin D receptors, estrogen receptors, estrogen-related receptors, and peroxisome proliferator-activated receptors) in linking immunity and autophagy during infection. We also discuss the potential of emerging NRs (REV-ERBs, retinoic acid receptors, retinoic acid-related orphan receptors, liver X receptors, farnesoid X receptors, and thyroid hormone receptors) as candidate antimicrobials. The identification of novel roles and mechanisms for NRs will enable the development of autophagy-adjunctive therapeutics for emerging and re-emerging infectious diseases.

Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor

1997 ◽  
Vol 19 (3) ◽  
pp. 207-226 ◽  
Author(s):  
V Laudet
Keyword(s):  
Hormone Receptors ◽  
Steroid Receptors ◽  
Distance Matrix ◽  
Nuclear Hormone Receptor ◽  
Orphan Receptor ◽  
Peroxisome Proliferator ◽  
Orphan Receptors ◽  
Vitamin D Receptors ◽  
Peroxisome Proliferator Activated Receptors ◽  
X Receptors

From a database containing the published nuclear hormone receptor (NR) sequences I constructed an alignment of the C, D and E domains of these molecules. Using this alignment, I have performed tree reconstruction using both distance matrix and parsimony analysis. The robustness of each branch was estimated using bootstrap resampling methods. The trees constructed by these two methods gave congruent topologies. From these analyses I defined six NR subfamilies: (i) a large one clustering thyroid hormone receptors (TRs), retinoic acid receptors (RARs), peroxisome proliferator-activated receptors (PPARs), vitamin D receptors (VDRs) and ecdysone receptors (EcRs) as well as numerous orphan receptors such as RORs or Rev-erbs; (ii) one containing retinoid X receptors (RXRs) together with COUP, HNF4, tailless, TR2 and TR4 orphan receptors; (iii) one containing steroid receptors; (iv) one containing the NGFIB orphan receptors; (v) one containing FTZ-F1 orphan receptors; and finally (vi) one containing to date only one gene, the GCNF1 orphan receptor. The relationships between the six subfamilies are not known except for subfamilies I and IV which appear to be related. Interestingly, most of the liganded receptors appear to be derived when compared with orphan receptors. This suggests that the ligand-binding ability of NRs has been gained by orphan receptors during the course of evolution to give rise to the presently known receptors. The distribution into six subfamilies correlates with the known abilities of the various NRs to bind to DNA as homo- or heterodimers. For example, receptors heterodimerizing efficiently with RXR belong to the first or the fourth subfamilies. I suggest that the ability to heterodimerize evolved once, just before the separation of subfamilies I and IV and that the first NR was able to bind to DNA as a homodimer. From the study of NR sequences existing in vertebrates, arthropods and nematodes, I define two major steps of NR diversification: one that took place very early, probably during the multicellularization event leading to all the metazoan phyla, and a second occurring later on, corresponding to the advent of vertebrates. Finally, I show that in vertebrate species the various groups of NRs accumulated mutations at very different rates.

scholarly journals New retinoid X receptor subtypes in zebra fish (Danio rerio) differentially modulate transcription and do not bind 9-cis retinoic acid.

1995 ◽  
Vol 15 (10) ◽  
pp. 5226-5234 ◽  
Author(s):  
B B Jones ◽  
C K Ohno ◽  
G Allenby ◽  
M B Boffa ◽  
A A Levin ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Dominant Negative ◽  
Cdna Libraries ◽  
Receptor Subtypes ◽  
Peroxisome Proliferator ◽  
Zebra Fish ◽  
Peroxisome Proliferator Activated Receptors ◽  
X Receptors

Retinoid X receptors (RXRs), along with retinoic acid (RA) receptors (RARs), mediate the effects of RA on gene expression. Three subtypes of RXRs (alpha, beta, and gamma) which bind to and are activated by the 9-cis stereoisomer of RA have been characterized. They activate gene transcription by binding to specific sites on DNA as homodimers or as heterodimers with RARs and other related nuclear receptors, including the vitamin D receptor, thyroid hormone receptors (TRs), and peroxisome proliferator-activated receptors. Two additional RXR subtypes (delta and epsilon) isolated from zebra fish cDNA libraries are described here; although both subtypes form DNA-binding heterodimers with RARs and TR, neither binds 9-cis RA, and both are transcriptionally inactive on RXR response elements. In cotransfection studies with TR, the delta subtype was found to function in a dominant negative manner, while the epsilon subtype had a slight stimulatory effect on thyroid hormone (T3)-dependent transcriptional activity. The discovery of these two novel receptors in zebra fish expands the functional repertoire of RXRs to include ligand-independent and dominant negative modulation of type II receptor function.

scholarly journals Nongenomic signaling of the retinoid X receptor through binding and inhibiting Gq in human platelets

Blood ◽  
2007 ◽  
Vol 109 (9) ◽  
pp. 3741-3744 ◽  
Author(s):  
Leonardo A. Moraes ◽  
Karen E. Swales ◽  
Jessica A. Wray ◽  
Amilcar Damazo ◽  
Jonathan M. Gibbins ◽  
...  
Keyword(s):  
G Protein ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Hormone Receptors ◽  
Calcium Release ◽  
Human Platelets ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
X Receptors

Abstract Retinoid X receptors (RXRs) are important transcriptional nuclear hormone receptors, acting as either homodimers or the binding partner for at least one fourth of all the known human nuclear receptors. Functional nongenomic effects of nuclear receptors are poorly understood; however, recently peroxisome proliferator-activated receptor (PPAR) \#947;, PPAR\#946;, and the glucocorticoid receptor have all been found active in human platelets. Human platelets express RXR\#945; and RXR\#946;. RXR ligands inhibit platelet aggregation and TXA2 release to ADP and the TXA2 receptors, but only weakly to collagen. ADP and TXA2 both signal via the G protein, Gq. RXR rapidly binds Gq but not Gi/z/o/t/gust in a ligand-dependent manner and inhibits Gq-induced Rac activation and intracellular calcium release. We propose that RXR ligands may have beneficial clinical actions through inhibition of platelet activation. Furthermore, our results demonstrate a novel nongenomic mode for nuclear receptor action and a functional cross-talk between G-protein and nuclear receptor signaling families.

scholarly journals PPARs and Metabolic Disorders Associated with Challenged Adipose Tissue Plasticity

2018 ◽  
Vol 19 (7) ◽  
pp. 2124 ◽  
Author(s):  
Patricia Corrales ◽  
Antonio Vidal-Puig ◽  
Gema Medina-Gómez
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Transcriptional Control ◽  
Hormone Receptors ◽  
Therapeutic Potential ◽  
Metabolic Stress ◽  
Regulatory Elements ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptors ◽  
X Receptors

Peroxisome proliferator-activated receptors (PPARs) are members of a family of nuclear hormone receptors that exert their transcriptional control on genes harboring PPAR-responsive regulatory elements (PPRE) in partnership with retinoid X receptors (RXR). The activation of PPARs coordinated by specific coactivators/repressors regulate networks of genes controlling diverse homeostatic processes involving inflammation, adipogenesis, lipid metabolism, glucose homeostasis, and insulin resistance. Defects in PPARs have been linked to lipodystrophy, obesity, and insulin resistance as a result of the impairment of adipose tissue expandability and functionality. PPARs can act as lipid sensors, and when optimally activated, can rewire many of the metabolic pathways typically disrupted in obesity leading to an improvement of metabolic homeostasis. PPARs also contribute to the homeostasis of adipose tissue under challenging physiological circumstances, such as pregnancy and aging. Given their potential pathogenic role and their therapeutic potential, the benefits of PPARs activation should not only be considered relevant in the context of energy balance-associated pathologies and insulin resistance but also as potential relevant targets in the context of diabetic pregnancy and changes in body composition and metabolic stress associated with aging. Here, we review the rationale for the optimization of PPAR activation under these conditions.

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