Abstract
Interferon (IFN)-stimulated genes (ISGs) play crucial roles in the antiviral immune response; however, IFNs also induce negative regulators that attenuate the antiviral response. Here, we show that both viral and bacterial invasion downregulate Nuclear Dbf2-related kinase 1 (NDR1) expression via the type I IFN signaling pathway. NDR1 promotes the virus-induced production of type I IFN, proinflammatory cytokines and ISGs in a kinase-independent manner. NDR1 deficiency also renders mice more susceptible to viral and bacterial infections. Mechanistically, NDR1 enhances STAT1 translation by directly binding to the intergenic region of miR146a, thereby inhibiting miR146a expression and liberating STAT1 from miR146a-mediated translational inhibition. Furthermore, STAT1 binds to the miR146a promoter, thus decreasing its expression. Together, our results suggest that NDR1 promotion of STAT1 translation is an important event for IFN-dependent antiviral immune response, and suggest that NDR1 has an important role in controlling viral infections.
Highlights
Interferon (IFN)-stimulated genes (ISGs) play crucial roles in the antiviral immune response; IFNs induce negative regulators that attenuate the antiviral response
Downregulated Nuclear Dbf2-related kinase 1 (NDR1) mRNA and protein levels were observed in mouse peritoneal macrophages (PMs) infected with RNA viruses, including respiratory syncytial virus (RSV) and vesicular stomatitis virus (VSV), and DNA viruses, including herpes simplex virus 1 (HSV) and murine herpes virus 68 (MHV68) (Fig. 1b, c)
NDR1 expression was decreased in human primary peripheral blood mononuclear cells (PBMCs) and various macrophages infected with VSV, including human acute monocytic leukemia cell line Thp[1], murine bone marrow-derived macrophages (BMDMs) and RAW264.7 (Supplementary Fig. 1a, b)
Summary
Interferon (IFN)-stimulated genes (ISGs) play crucial roles in the antiviral immune response; IFNs induce negative regulators that attenuate the antiviral response. STAT1 binds to the miR146a promoter, decreasing its expression. Our results suggest that NDR1 promotion of STAT1 translation is an important event for IFN-dependent antiviral immune response, and suggest that NDR1 has an important role in controlling viral infections. Given the important roles of miR146a in innate antiviral immune responses, the delicate mechanism by which miR146a is regulated after viral infection requires further investigation. NDR1 binds to the intergenic region of miR146a and compromises NF-κB-mediated miR146a transcription, enhancing STAT1 translation. STAT1 binds to the miR146a promoter, thereby further inhibiting NF-κB-mediated miR146a transcription. Our data demonstrate that viral infection downregulates NDR1 expression, counteracting the mutual inhibition between miR146a and STAT1 and resulting in decreased STAT1 expression and impaired ISG expression, thereby allowing viral escape from innate immunity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
