The alternative cap-binding complex is required for antiviral defense in vivo

Anna Gebhardt; Valter Bergant; Daniel Schnepf; Markus Moser; Arno Meiler; Dieudonnée Togbe; Claire Mackowiak; Line S Reinert; Søren R Paludan; Bernhard Ryffel; Alexey Stukalov; Peter Staeheli; Andreas Pichlmair

doi:10.1371/journal.ppat.1008155

The alternative cap-binding complex is required for antiviral defense in vivo

PLoS Pathog. 2019 Dec 19;15(12):e1008155. doi: 10.1371/journal.ppat.1008155. eCollection 2019 Dec.

Authors

Anna Gebhardt^{1

2}, Valter Bergant^{1

2}, Daniel Schnepf^{3

4}, Markus Moser^{5

6}, Arno Meiler², Dieudonnée Togbe⁷, Claire Mackowiak⁷, Line S Reinert⁸, Søren R Paludan⁸, Bernhard Ryffel^{7

9}, Alexey Stukalov^{1

2}, Peter Staeheli^{3

10}, Andreas Pichlmair^{1

2

11}

Affiliations

¹ Institute of Virology, Technical University of Munich, School of Medicine, Munich, Germany.
² Innate Immunity Laboratory, Max-Planck Institute of Biochemistry, Martinsried, Germany.
³ Institute of Virology, University of Freiburg, Freiburg, Germany.
⁴ Spemann Graduate School of Biology and Medicine, Albert Ludwigs University Freiburg, Freiburg, Germany.
⁵ Department of Molecular Medicine, Max-Planck Institute of Biochemistry, Martinsried, Germany.
⁶ Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technical University of Munich, Munich, Germany.
⁷ INEM, Experimental Molecular Immunology, UMR7355 CNRS and University, Orleans, France.
⁸ Department of Biomedicine, University of Aarhus, Aarhus, Denmark.
⁹ Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
¹⁰ Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹¹ German Center for Infection Research (DZIF), Munich partner site, Munich, Germany.

Abstract

Cellular response to environmental challenges requires immediate and precise regulation of transcriptional programs. During viral infections, this includes the expression of antiviral genes that are essential to combat the pathogen. Transcribed mRNAs are bound and escorted to the cytoplasm by the cap-binding complex (CBC). We recently identified a protein complex consisting of NCBP1 and NCBP3 that, under physiological conditions, has redundant function to the canonical CBC, consisting of NCBP1 and NCBP2. Here, we provide evidence that NCBP3 is essential to mount a precise and appropriate antiviral response. Ncbp3-deficient cells allow higher virus growth and elicit a reduced antiviral response, a defect happening on post-transcriptional level. Ncbp3-deficient mice suffered from severe lung pathology and increased morbidity after influenza A virus challenge. While NCBP3 appeared to be particularly important during viral infections, it may be more broadly involved to ensure proper protein expression.

Publication types

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

MeSH terms

Animals
Influenza A virus / immunology
Mice
Mice, Knockout
Orthomyxoviridae Infections / immunology*
Orthomyxoviridae Infections / metabolism
Protein Biosynthesis / physiology
RNA Cap-Binding Proteins / immunology*
RNA Cap-Binding Proteins / metabolism*

Substances

RNA Cap-Binding Proteins

Grants and funding

This work was supported by the Max-Planck Free Floater program to A.P., the German research foundation to A.P. (PI1084/3 and TRR179 TP11) and P.S. (SFB 1160, project 13), the Lunbeck Foundation to L.R. (R198 2015 171), the Centre National de la Recherche Scientifique (CNRS), University and European Regional Development Fund (FEDER (N° 2016-00110366 and EX005756) to B.R., an ERC consolidator grant to A.P (ERC CoG ProDAP, 817798) and the Infect-Era and the German Federal Ministry of Education and Research (ERASE) to A.P. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.