NONO Detects the Nuclear HIV Capsid to Promote cGAS-Mediated Innate Immune Activation

Xavier Lahaye; Matteo Gentili; Aymeric Silvin; Cécile Conrad; Léa Picard; Mabel Jouve; Elina Zueva; Mathieu Maurin; Francesca Nadalin; Gavin J Knott; Baoyu Zhao; Fenglei Du; Marlène Rio; Jeanne Amiel; Archa H Fox; Pingwei Li; Lucie Etienne; Charles S Bond; Laurence Colleaux; Nicolas Manel

doi:10.1016/j.cell.2018.08.062

NONO Detects the Nuclear HIV Capsid to Promote cGAS-Mediated Innate Immune Activation

Cell. 2018 Oct 4;175(2):488-501.e22. doi: 10.1016/j.cell.2018.08.062. Epub 2018 Sep 27.

Authors

Xavier Lahaye¹, Matteo Gentili¹, Aymeric Silvin¹, Cécile Conrad¹, Léa Picard², Mabel Jouve¹, Elina Zueva¹, Mathieu Maurin¹, Francesca Nadalin¹, Gavin J Knott³, Baoyu Zhao⁴, Fenglei Du⁴, Marlène Rio⁵, Jeanne Amiel⁵, Archa H Fox⁶, Pingwei Li⁴, Lucie Etienne⁷, Charles S Bond³, Laurence Colleaux⁵, Nicolas Manel⁸

Affiliations

¹ Immunity and Cancer Department, Institut Curie, PSL Research University, INSERM U932, 75005 Paris, France.
² CIRI-International Center for Infectiology Research, Inserm U1111, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon 1, Univ Lyon, 69007 Lyon, France; LBBE-Laboratoire de Biométrie et Biologie Evolutive CNRS UMR 5558, Universite Lyon 1, Univ Lyon, 69622 Villeurbanne, France.
³ School of Molecular Sciences, The University of Western Australia, Crawley, WA 6009, Australia.
⁴ Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
⁵ INSERM UMR 1163, Paris-Descartes-Sorbonne Paris Cité University, Institut IMAGINE, Necker-Enfants Malades Hospital, 75015 Paris, France; Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
⁶ School of Molecular Sciences, The University of Western Australia, Crawley, WA 6009, Australia; School of Human Sciences, The University of Western Australia, Crawley, WA 6009, Australia; The Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA 6009, Australia.
⁷ CIRI-International Center for Infectiology Research, Inserm U1111, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon 1, Univ Lyon, 69007 Lyon, France.
⁸ Immunity and Cancer Department, Institut Curie, PSL Research University, INSERM U932, 75005 Paris, France. Electronic address: nicolas.manel@curie.fr.

PMID: 30270045
DOI: 10.1016/j.cell.2018.08.062

Abstract

Detection of viruses by innate immune sensors induces protective antiviral immunity. The viral DNA sensor cyclic GMP-AMP synthase (cGAS) is necessary for detection of HIV by human dendritic cells and macrophages. However, synthesis of HIV DNA during infection is not sufficient for immune activation. The capsid protein, which associates with viral DNA, has a pivotal role in enabling cGAS-mediated immune activation. We now find that NONO is an essential sensor of the HIV capsid in the nucleus. NONO protein directly binds capsid with higher affinity for weakly pathogenic HIV-2 than highly pathogenic HIV-1. Upon infection, NONO is essential for cGAS activation by HIV and cGAS association with HIV DNA in the nucleus. NONO recognizes a conserved region in HIV capsid with limited tolerance for escape mutations. Detection of nuclear viral capsid by NONO to promote DNA sensing by cGAS reveals an innate strategy to achieve distinction of viruses from self in the nucleus.

Keywords: HIV-1; HIV-2; NONO; STING; cGAS; capsid; dendritic cells; innate immune sensors; innate immunity; macrophages.

Publication types

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

MeSH terms

Capsid / metabolism
Capsid Proteins / immunology*
Capsid Proteins / metabolism
Capsid Proteins / physiology
Cell Nucleus / metabolism
DNA, Viral / genetics
DNA, Viral / immunology
DNA-Binding Proteins
Dendritic Cells / immunology
HIV Infections / immunology
HIV-1 / genetics
HIV-1 / immunology
HIV-2 / genetics
HIV-2 / immunology
Host-Pathogen Interactions
Humans
Immunity, Innate / immunology
Macrophages / immunology
Membrane Proteins / metabolism
Nuclear Matrix-Associated Proteins / immunology*
Nuclear Matrix-Associated Proteins / metabolism
Nuclear Matrix-Associated Proteins / physiology*
Nucleotidyltransferases / metabolism
Nucleotidyltransferases / physiology
Octamer Transcription Factors / immunology*
Octamer Transcription Factors / physiology*
RNA-Binding Proteins / immunology*
RNA-Binding Proteins / metabolism
RNA-Binding Proteins / physiology*
Signal Transduction / immunology

Substances

Capsid Proteins
DNA, Viral
DNA-Binding Proteins
Membrane Proteins
NONO protein, human
Nuclear Matrix-Associated Proteins
Octamer Transcription Factors
RNA-Binding Proteins
Nucleotidyltransferases
cGAS protein, human