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

Date Published: June 7, 2017

Publisher: Public Library of Science

Author(s): Xiang He, Shengli Ma, Yinyin Tian, Congwen Wei, Yongjie Zhu, Feng Li, Pingping Zhang, Penghao Wang, Yanhong Zhang, Hui Zhong, Christopher F. Basler.

http://doi.org/10.1371/journal.ppat.1006347

Abstract

Estrogen-related receptor α (ERRα) is a member of the nuclear receptor superfamily controlling energy homeostasis; however, its precise role in regulating antiviral innate immunity remains to be clarified. Here, we showed that ERRα deficiency conferred resistance to viral infection both in vivo and in vitro. Mechanistically, ERRα inhibited the production of type-I interferon (IFN-I) and the expression of multiple interferon-stimulated genes (ISGs). Furthermore, we found that viral infection induced TBK1-dependent ERRα stabilization, which in turn associated with TBK1 and IRF3 to impede the formation of TBK1-IRF3, IRF3 phosphorylation, IRF3 dimerization, and the DNA binding affinity of IRF3. The effect of ERRα on IFN-I production was independent of its transcriptional activity and PCG-1α. Notably, ERRα chemical inhibitor XCT790 has broad antiviral potency. This work not only identifies ERRα as a critical negative regulator of antiviral signaling, but also provides a potential target for future antiviral therapy.

Partial Text

The innate immune system plays important roles in the detection and elimination of invading pathogens. The host senses viral and bacterial pathogen invasion via the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) and cytosolic sensory molecules, such as RIG-like receptors (RLRs) and NOD-like receptors (NLRs). These then activate a series of signal cascades, leading to the production of IFN-I and proinflammatory cytokines. Upon viral infection, TLRs detect pathogen nucleic acids in the lumen of endosomes, whereas RLRs, DAI, IFI16, LRRFIP1 and cGAS sense pathogen nucleic acids in the cytoplasm [1–5]. TLRs-mediated signaling pathways associate with the adaptor protein MyD88 and TRIF, while RLRs recruit MAVS and STING. Both pathways ultimately converge on the activation of TBK1 upon adaptor recruitment. Activated TBK1 then phosphorylates IRF3, IRF5 and IRF7, triggers their dimerization and nuclear translocation, and activates IFN-I expression. Secreted IFN-α/β further activates downstream signaling pathways to induce a wide range of antiviral genes and elicit cellular antiviral responses.

Innate immunity and metabolism appear to be inextricably linked and are now known to regulate each other reciprocally [16,40–42]. Exciting new evidence is emerging with regard to the role of TLRs and NLRs in the regulation of metabolism and the activation of inflammatory pathways during the progression of metabolic disorders, such as type 2 diabetes [43] and Reye’s syndrome [44]. Studies have also suggested that metabolites, such as 25-HC [45–47], NAD [48] (acting via deacetylases such as SIRT1 and SIRT2) and succinate [49] (which regulates hypoxia-inducible factor 1), regulate innate immunity. Additionally, extracellular overproduction of metabolites, such as uric acid and cholesterol crystals, is sensed by NLRP3, leading to activation of the inflammasome complex and the production of IL-1β [50,51]. In turn, some nuclear receptors reported to regulate metabolism, such as the glucocorticoid receptor (GR) [52], peroxisome proliferator-activated receptor γ (PPAR-γ) [53] and retinoid X receptor α (RXRα) [54], have been implicated in type I interferon regulation. The interplay between immunity and metabolic changes is a growing field of research.

 

Source:

http://doi.org/10.1371/journal.ppat.1006347

 

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