Downregulated NDR1 protein kinase inhibits innate immune response by initiating an miR146a-STAT1 feedback loop

Zhiyong Liu; Qiang Qin; Cheng Wu; Hui Li; Jia'nan Shou; Yuting Yang; Meidi Gu; Chunmei Ma; Wenlong Lin; Yan Zou; Yuanyuan Zhang; Feng Ma; Jihong Sun; Xiaojian Wang

doi:10.1038/s41467-018-05176-7

Downregulated NDR1 protein kinase inhibits innate immune response by initiating an miR146a-STAT1 feedback loop

Nat Commun. 2018 Jul 17;9(1):2789. doi: 10.1038/s41467-018-05176-7.

Authors

Zhiyong Liu¹, Qiang Qin¹, Cheng Wu¹, Hui Li², Jia'nan Shou¹, Yuting Yang¹, Meidi Gu¹, Chunmei Ma¹, Wenlong Lin¹, Yan Zou³, Yuanyuan Zhang⁴, Feng Ma⁵, Jihong Sun⁶, Xiaojian Wang⁷

Affiliations

¹ Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, 310058, PR China.
² Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, 310022, PR China.
³ Medical Science Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, 545005, PR China.
⁴ The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, PR China.
⁵ Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, PR China.
⁶ Department of Radiology, Sir Run Run Shaw Hospital School of Medicine, Zhejiang University, Hangzhou, 310058, PR China. [email protected].
⁷ Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, 310058, PR China. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bronchiolitis, Viral / genetics*
Bronchiolitis, Viral / immunology
Bronchiolitis, Viral / virology
Case-Control Studies
Child
Feedback, Physiological*
Gene Expression Regulation
HEK293 Cells
Herpesvirus 1, Human / genetics*
Herpesvirus 1, Human / immunology
Host-Pathogen Interactions
Humans
Immunity, Innate
Interferon-alpha / genetics
Interferon-alpha / immunology
Interferon-beta / genetics
Interferon-beta / immunology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
MicroRNAs / genetics*
MicroRNAs / immunology
Protein Biosynthesis
Protein Serine-Threonine Kinases / deficiency
Protein Serine-Threonine Kinases / genetics*
Protein Serine-Threonine Kinases / immunology
RAW 264.7 Cells
Respiratory Syncytial Virus, Human / genetics
Respiratory Syncytial Virus, Human / immunology
STAT1 Transcription Factor / genetics*
STAT1 Transcription Factor / immunology
Signal Transduction
Vesicular stomatitis Indiana virus / genetics*
Vesicular stomatitis Indiana virus / immunology

Substances

Interferon-alpha
MicroRNAs
Mirn146 microRNA, mouse
STAT1 Transcription Factor
Stat1 protein, mouse
Interferon-beta
NDR1 protein kinase, mouse
Protein Serine-Threonine Kinases