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Influenza virus NS1- C/EBPβ gene regulatory complex inhibits RIG-I transcription

Kumari R 1 , Guo Z 2 , Kumar A 1 , Wiens M 2 , Gangappa S 2 , Katz JM 2 Show all authors , Cox NJ 2 , Lal RB 2 , Sarkar D 3 , Fisher PB 3 , García-Sastre A 4 , Fujita T 5 , Kumar V 6 , Sambhara S 2 , Ranjan P 7 , Lal SK 8

Affiliations 

  • 1 Virology Group, International Centre for Genetic Engineering & Biotechnology, New Delhi, 110067, India
  • 2 Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
  • 3 Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine and VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA
  • 4 Department of Microbiology, Department of Medicine Division of Infectious Diseases and Global Health, Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
  • 5 Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto, Japan
  • 6 Virology Group, International Centre for Genetic Engineering & Biotechnology, New Delhi, 110067, India; Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences (ILBS), New Delhi, 110070, India
  • 7 Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA. Electronic address: pranjan@cdc.gov
  • 8 Virology Group, International Centre for Genetic Engineering & Biotechnology, New Delhi, 110067, India; School of Science, Tropical Medicine and Biology Multidisciplinary Plateform, Monash University Malaysia, 47500, Bandar Sunway, Selangor DE, Malaysia. Electronic address: sunil.lal@gmail.monash.edu
Antiviral Res, 2020 Apr;176:104747.
PMID: 32092305 DOI: 10.1016/j.antiviral.2020.104747

Abstract

Influenza virus non-structural protein 1 (NS1) counteracts host antiviral innate immune responses by inhibiting Retinoic acid inducible gene-I (RIG-I) activation. However, whether NS1 also specifically regulates RIG-I transcription is unknown. Here, we identify a CCAAT/Enhancer Binding Protein beta (C/EBPβ) binding site in the RIG-I promoter as a repressor element, and show that NS1 promotes C/EBPβ phosphorylation and its recruitment to the RIG-I promoter as a C/EBPβ/NS1 complex. C/EBPβ overexpression and siRNA knockdown in human lung epithelial cells resulted in suppression and activation of RIG-I expression respectively, implying a negative regulatory role of C/EBPβ. Further, C/EBPβ phosphorylation, its interaction with NS1 and occupancy at the RIG-I promoter was associated with RIG-I transcriptional inhibition. These findings provide an important insight into the molecular mechanism by which influenza NS1 commandeers RIG-I transcriptional regulation and suppresses host antiviral responses.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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