ERRα negatively regulates type I interferon induction by inhibiting TBK1-IRF3 interaction

He, Xiaoqing; Ma, Shengli; Tian, Yinyin; Wei, Congwen; Zhu, Yongjie; Li, Feng; Zhang, Pingping; Wang, Penghao; Zhang, Yanhong; Zhong, Hui

doi:10.1371/journal.ppat.1006347

Cited by 21 publications

(16 citation statements)

References 63 publications

(65 reference statements)

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“…In addition, as a substrate of TBK1, SIKE also interacts with TBK1 with a higher affinity and thus suppresses TBK1-catalyzed IRF3 phosphorylation [84]. Protein arginine methyltransferases 6 (PRMT6) [85] and estrogen-related receptor α (ERRα) [86] inhibit the association of TBK1 and its substrate IRF3, resulting in turning off the transmission of the active TBK1 signal to IRF3.…”

Section: Formation Of Functional Tbk1-containing Complexesmentioning

confidence: 99%

“…In addition, other small molecules targeting TBK1/IFN pathway were used to modulate antiviral responses. As ERRα could associate with TBK1 and IRF3 to impede the formation of TBK1-IRF3 complex, ERRα chemical inhibitor XCT790 shows broad antiviral potency [86]. A KALA-modified lipid nanoparticle containing CpG-free plasmid DNA could function as a potential immune-stimulative DNA vaccine carrier, which activates the STING/TBK1 pathway to produce IFN-β against viral infection [112].…”

Section: Implications In Antiviral Drugsmentioning

confidence: 99%

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TANK-binding kinase 1 as a novel therapeutic target for viral diseases

Zhao

2019

Expert Opinion on Therapeutic Targets

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Introduction: TANK-binding kinase 1 (TBK1) is vital for the induction of antiviral innate immune responses. Both RNA and DNA viral infection induces TBK1 activation, triggers phosphorylation of interferon regulatory factor (IRF) 3 and subsequent expression of type I interferons (IFNs; IFN-α/β). Type I IFNs can induce the expression of numerous antiviral genes called interferon-stimulated genes (ISGs) to build a remarkable antiviral state and limit viral replication. Thus, optimal TBK1 activity is crucial for IRF3-induced type I IFNs expression and ISGs-mediated viral elimination. Areas covered: This review provides an overview of the diverse roles of TBK1 in antiviral innate immune responses, the regulatory mechanisms of TBK1 activity and the implication in antiviral development. Expert opinion: TBK1 is a key kinase against antiviral infection via inducing type I IFNs expression. Multiple types of post-translational modifications of TBK1 tightly regulate TBK1 activity and subsequent TBK1-dependent antiviral responses. The identified regulators of TBK1 unveil regulatory mechanisms of host antiviral innate immunity and immuno-escape mechanism of virus provide strategies to control viral diseases by modulating TBK1 activity.

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Section: Formation Of Functional Tbk1-containing Complexesmentioning

confidence: 99%

Section: Implications In Antiviral Drugsmentioning

confidence: 99%

TANK-binding kinase 1 as a novel therapeutic target for viral diseases

Zhao

2019

Expert Opinion on Therapeutic Targets

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“…Additionally, Polo-like kinase (PLK) 2 is associated with IRF3 nuclear translocation (8). In contrast, multiple proteins, including PIN1, YAP, RBCK1, RAUL, PTEN, PP2A, MAPK phosphatase 5, SENP2, TRIM21 (Ro52), TRIM26, FoxO1, c-cbl, Rubicon, ERRa, MST1, and AGO2, have been reported to negatively regulate IRF3 activation via distinct mechanisms such as proteasome-dependent degradation, dephosphorylation, de-SUMOylation, and/or prevention of protein-protein interactions (9)(10)(11)(12)(13)(14)(15)(16)(17)(18).…”

mentioning

confidence: 99%

Hu Antigen R Regulates Antiviral Innate Immune Responses through the Stabilization of mRNA for Polo-like Kinase 2

Sueyoshi

Kawasaki

Kitai

et al. 2018

The Journal of Immunology

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Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), RIG-I, and melanoma differentiation-associated gene 5 (MDA5) play a critical role in inducing antiviral innate immune responses by activating IFN regulatory factor 3 (IRF3) and NF-κB, which regulates the transcription of type I IFN and inflammatory cytokines. Antiviral innate immune responses are also regulated by posttranscriptional and translational mechanisms. In this study, we identified an RNA-binding protein HuR as a regulator for RLR signaling. Overexpression of HuR, but not of other Hu members, increased IFN-β promoter activity. HuR-deficient macrophage cells exhibited decreased expression after RLR stimulation, whereas they showed normal induction after stimulation with bacterial LPS or immunostimulatory DNA. Moreover, HuR-deficient cells displayed impaired nuclear translocation of IRF3 after RLR stimulation. In HuR-deficient cells, the mRNA expression of Polo-like kinase (PLK) 2 was markedly reduced. We found that HuR bound to the 3' untranslated region of mRNA and increased its stabilization. PLK2-deficient cells also showed reduced IRF3 nuclear translocation and mRNA expression during RLR signaling. Together, these findings suggest that HuR bolsters RLR-mediated IRF3 nuclear translocation by controlling the stability of mRNA.

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“…In contrast, the inhibition of ERRα activity by the inverse agonist XCT790 induced autophagy and promoted the clearance of toxic protein aggregates, enhancing its neuroprotective effect [ 139 ]. There is a role for ERRα in host defense between intracellular bacteria and viruses [ 23 , 140 , 141 , 142 ]. Therefore, future studies should clarify the role of ERRα in modulating autophagy and evaluate its therapeutic potential as an antimicrobial.…”

Section: Estrogen-related Receptorsmentioning

confidence: 99%

Nuclear Receptors as Autophagy-Based Antimicrobial Therapeutics

Silwal

Paik

Jeon

et al. 2020

Cells

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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.

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ERRα negatively regulates type I interferon induction by inhibiting TBK1-IRF3 interaction

Cited by 21 publications

References 63 publications

TANK-binding kinase 1 as a novel therapeutic target for viral diseases

TANK-binding kinase 1 as a novel therapeutic target for viral diseases

Hu Antigen R Regulates Antiviral Innate Immune Responses through the Stabilization of mRNA for Polo-like Kinase 2

Nuclear Receptors as Autophagy-Based Antimicrobial Therapeutics

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