Nuclear Receptors as Autophagy-Based Antimicrobial Therapeutics
Abstract
:1. Introduction
2. Overview of Autophagy and Autophagy-Related Genes
3. Overview of Nuclear Receptors
4. Vitamin D Receptor in Autophagy-Mediated Defense against Infection
5. Estrogen Receptors
6. Estrogen-Related Receptors
7. Peroxisome Proliferator-Activated Receptors
7.1. Peroxisome Proliferator-Activated Receptor-α
7.2. PPARβ/δ and PPARγ
8. Other Nuclear Receptors Potentially Linking Autophagy and Host Defenses
8.1. REV-ERBα and REV-ERBβ
8.2. Retinoic Acid Receptor-α (RARα; RARA; NR1B1), -β (RARβ; RARB; NR1B2), and -γ (RARγ; RARG; NR1B3)
8.3. Retinoic Acid-Related Orphan-α (RORα; RORA; NR1F1), -β (RORβ; RORB; NR1F2), and -γ (RORγ; RORC; NR1F3)
8.4. Farnesoid X Receptors-α (FXR-α)
8.5. Liver X Receptor (LXR)-α (LXRα; NR1H3) and -β (LXRβ; NR1H2)
8.6. Thyroid Hormone Receptors-α (TRα; THRA; NR1A1) and -β (TRβ; THRB; NR1A2)
9. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Ligand/Activator | Pathogen/Disease | Study Model | Autophagy | Effects | Mechanism of Action | Ref. |
---|---|---|---|---|---|---|
Bacterial/Fungal infections | ||||||
Vit-D | H. pylori | Human gastric epithelial cell lines, clinical specimens | ↑ | Bacterial eradication | Activation of PDIA3 receptor and nuclear translocation of PDIA3-STAT3 complex to induce autophagosomal degradation independent of VDR | [106] |
Mtb | Human primary monocytes, MDMs, THP-1, and RAW264.7 cells | ↑ | Antimicrobial | Beclin-1 and Atg-5 activation mediated through hCAP-18/LL-37-dependent MAPK and C/EBPβ activation | [107] | |
PGE2, human macrophages | ↓ | Intracellular Mtb survival | PGE2 inhibits hCAP18/LL-37 expression and vitamin D-induced cathelicidin and autophagy by dampening expression of VDR | [114] | ||
Mouse model | ↑ | Antimicrobial | Vit-D supplementation on 2nd-line anti-TB therapy leads to suppression of MMP1 Induction of VDR, CRAMP, LC3B, and caspase-3 | [115] | ||
IFN-γ, human macrophages | ↑ | Antimicrobial | Vitamin D-dependent autophagy and autophagolysosomal fusion by IFN-γ VDR-dependent induction of cathelicidin and DEFB4 by IFN-γ | [121] | ||
A. fumigatus | Alveolar macrophages | ↓ | Antimicrobial | Delayed formation of lysosomes against infection Modulation of Dectin-1, ROS, and LC3 expression | [127] | |
M. marinum | Human monocytes (THP-1) | ↑ | Antibacterial | Induction of endogenous CAMP and its colocalization with autophagolysosome | [110] | |
Vit-D-sufficient human serum | Mtb | CD40L, IFN-γ, human PBMC | ↑ | Antimicrobial | Induction of CYP27B1, VDR, cathelicidin, and DEFB4 | [122] |
- | Mtb lipoprotein LpqH | Human primary monocytes | ↑ | Antibacterial | TLR2/1/CD14-mediated (C/EBP)-β-dependent induction of CYP27B1 | [109] |
PBA+Vit-D | Mtb | PBMCs and MDMs from TB patients | ↑ | Antimicrobial | Increased LC3 expression, decreased XBP1spl mRNA | [116] |
TB patients | Clinical trial | - | Antimicrobial | Increased LL-37 | [117] | |
Clinical trial | - | Clinical recovery | Increased serum Vit-D levels after PBA+Vit-D supplementation | [118] | ||
LAB | S. enterica | HCT116, MEFs cell lines, in vivo mice | ↑ | Anti-inflammatory | Enhanced expression of Beclin-1 and ATG16L1 Increased expression of VDR and cathelicidin | [126] |
Viral infections | ||||||
Vit-D | HIV | Human MDMs | ↑ | Inhibition of virus replication | PI3K-, ATG-5-, and Beclin-1-dependent autophagy activation | [111] |
HIV, Mtb | Human MDMs | ↑ | Inhibition of virus replication and mycobacterial growth | Induced expression of CAMP | [112] | |
Influenza A | A549 cell lines | ↑ | Antiviral | Restoration of virus-induced inhibition of autophagic flux through Syntaxin-17 and ATP6V0A2 | [125] | |
Rotavirus | Pigs, IPEC-J2 cells | ↑ | Inhibition of virus infection | Regulation of autophagic maturation and expression of porcine cathelicidin genes | [128] | |
TLR8 ligands | HIV | Human macrophages | ↑ | Reduced virus replication | Induced expression of CAMP, VDR, and CYP27B1 | [113] |
NRs | Ligands/Activator | Pathogen/Study Model | Autophagy | Effects | Mechanism of Action | Ref. |
---|---|---|---|---|---|---|
ER | Estrogen (E2) | Thyroid cancer patients samples, Nthy-ori 3-1, PTC cell, BCPAP-ERα, MCF-7 cells | ↑ | Tumor cell survival | Generation of ROS, activation of ERK1/2 | [131] |
Bazedoxifene | Mtb/THP-1 cells | ↑ | Inhibition of intracellular growth of Mtb | Increased ROS and phosphorylation of Akt/mTOR signaling | [90] | |
ERRα | AICAR | Mtb/BMDMs, RAW264.7, HEK293T cells | ↑ | Antimicrobial host defense | Transcriptional activation of autophagy-related genes, and post transcriptional activation of autophagy through SIRT1 activation | [23] |
Thyroid hormone | THRB1-HepG2 cells, in vivo mice model | - | Mitophagy induction | Increased ESRRA expression via PPARGC1A Induction of ULK1 mRNA and protein through ESRRA-dependent transcription | [138] | |
XCT 790 | SH-SY5Y, HeLa cells, in vivo mice | ↑ | Neuroprotective | Regulation of autophagy by ERRα through its localization with autophagosome | [139] |
NRs | Ligands/Activator | Pathogen | Pathogen/Study Model | Autophagy | Effects | Mechanism of Action | Ref. |
---|---|---|---|---|---|---|---|
PPARα | GW7647, Wy14643 | Mtb | BMDMs, in vivo mice | ↑ | Antimicrobial | Increased expression and nuclear translocation of TFEB | [72] |
Gemfibrozil | M. abscessus | BMDMs, in vivo mice | ↑ | Antimicrobial | Increased nuclear translocation of TFEB | [70] | |
PPARβ/δ | GW501516 | - | Human cardiac AC16 cells, in vivo mice | ↑ | Inhibition of palmitate induced ER stress | Upregulation of Beclin-1 and LC3II | [155] |
PPARγ | HP24 | T. cruzi | Peritoneal macrophages, in vivo mice | - | Pro-angiogenic and anti-inflammatory | Induction of pro-angiogenic mediators (eNOS and VEGF-A) through PI3K/Akt/mTOR and PPARγ pathway Inhibition of NF-κB pathway in PPARγ-dependent manner | [159] |
INT131 | EcoHIV | Primary mouse glial cells, in vivo mice | - | Anti-inflammatory | Inhibition of proinflammatory cytokines | [160] |
NRs | Ligands/Activator | Pathogen/Study Model | Autophagy | Effects | Mechanism of Action | Ref. |
---|---|---|---|---|---|---|
REV-ERBα | GSK4122 | Zebrafish | Rhythmic with circadian clock | Regulation of autophagy rhythms | Direct regulation of NR1D1 and CEBPB by nutritional signals and circadian clock | [164] |
- | Mouse model, MEF, Hepa1-6 and HEK293 cells | Rhythmic with circadian clock | Regulation of autophagy rhythms | Autophagy activation through TFEB and TFE3; repression by REV-ERBα | [162] | |
GSK4112 | Mtb/Human macrophages | ↑ | Antimicrobial | Modulation of LAMP1 and TFEB, repression of IL10 | [165] | |
SR9009, SR9011 | Cancer cell lines, human glioblastoma stem cells, in vivo mice | ↓ | Anticancer | REV-ERB agonist inhibit autophagy (decreased LC3, increased p62, and increased LAMP1) and de novo lipogenesis to induce apoptotic responses | [163] | |
in vivo mice, C2C12 myoblasts | ↓ | Improved muscle oxidative function | LKB1-AMPK-SIRT1–PPARGC1A signaling pathway | [167] | ||
RARα | ATRA | HeLa, APL NB4 cells | ↑ | Differentiation of APL cells | Inhibition of mTOR pathway to induce autophagy-dependent PML/RARA degradation | [171] |
APL patients samples, NB4 cell lines | ↑ | Differentiation of APL cells | MIR125B1 overexpression enhanced PML-RARA expression DRAM2 as a target of MIR125B1 | [172] | ||
RORα | - | HPAIV (H5N1)/human monocytes, | - | Inhibition of inflammatory responses | H5N1 inhibits NF-κB and activates RORα in monocytes | [182] |
- | MI/R injury mice model | ↑ or preservation of autophagy function | Protection against MI/R injury | Inhibition of ER stress and mitochondrial apoptosis pathway, restoration of autophagy function, reduced oxidative/nitrative stress | [183] | |
RORγ | Melatonin | Human HL cell line L428 | ↑ | Cell death | Induction of autophagic cell death by melatonin via increased level of RORC | [192] |
FXR/PPARα | GW4064/GW7647 | Mouse primary hepatocytes, mouse liver | FXR: ↓, PPAR: ↑ | - | FXR and PPAR compete for binding to common sites in autophagic gene promotors, with opposite transcriptional outputs | [22] |
GW4064/GW7646, Wy14643 | Human RPE cells, MEFs, HK2, A549 cells | FXR: ↓, PPAR: ↑ | FXR represses and PPAR facilitates cliogenesis | Regulation of expression of autophagic genes, FXR acts in opposite way with PPARA | [143] | |
FXR | Bile acids | Liver tissue from cholestasis patients, HepG2 cells | ↓ | Autophagy and Rubicon could be novel treatment target for cholestatic liver disease | Prevention of proper fusion of autophagolysosome with lysosomes by bile acids, through FXR-dependent induction of Rubicon | [194] |
GW4064 | In vivo mice with hepatic deletion of Atg7 or Atg5 with or without Nrf2 codeletion | ↓ | Liver injury | NRF2 activation in autophagy deficiency leading to downregulation of FXR, causing cholestasis | [195] | |
LXR | T0901317, GW3965, LXR-623 | HBV/primary human hepatocytes, HepaRG cells | - | Anti-HBV effects | Inhibition of cholesterol 7α-hydroxylase 1 (CYP7A1) mRNA levels | [198] |
DDA | Melanoma and AML cell lines, AML patients samples, in vivo mice | ↑ | Anti-tumor | DDA acting as partial agonist on LRX to increase Nur77, Nor1, and LC3 expression | [204] | |
TR | T3 | HepG2, Huh7 cells | ↑ | Lipid metabolism | Upregulation of C19orf80 expression, which is involved in lipid metabolism through breakdown of lipid droplets | [208] |
Mice model of hepatocarcinogenesis, HepG2 cells | ↑ | Inhibition of hepatic DNA damage, inflammation, and carcinogenesis | Induction of hepatic PINK1 expression, which ubiquitinates HBx protein to trigger mitophagy | [209] |
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Silwal, P.; Paik, S.; Jeon, S.M.; Jo, E.-K. Nuclear Receptors as Autophagy-Based Antimicrobial Therapeutics. Cells 2020, 9, 1979. https://doi.org/10.3390/cells9091979
Silwal P, Paik S, Jeon SM, Jo E-K. Nuclear Receptors as Autophagy-Based Antimicrobial Therapeutics. Cells. 2020; 9(9):1979. https://doi.org/10.3390/cells9091979
Chicago/Turabian StyleSilwal, Prashanta, Seungwha Paik, Sang Min Jeon, and Eun-Kyeong Jo. 2020. "Nuclear Receptors as Autophagy-Based Antimicrobial Therapeutics" Cells 9, no. 9: 1979. https://doi.org/10.3390/cells9091979