SAMD9L protein, human; SAMD9 protein, human; Antiviral Restriction Factors; Intracellular Signaling Peptides and Proteins; Tumor Suppressor Proteins; Humans; Animals; HEK293 Cells; Protein Biosynthesis; Intracellular Signaling Peptides and Proteins/metabolism; Intracellular Signaling Peptides and Proteins/genetics; HIV Infections/virology; HIV Infections/drug therapy; HIV-1/genetics; HIV-1/physiology; Virus Replication; Lentiviruses, Primate/genetics; Lentiviruses, Primate/metabolism; HIV Infections; HIV-1; Lentiviruses, Primate; Neuroscience (all); Biochemistry, Genetics and Molecular Biology (all); Immunology and Microbiology (all); Agricultural and Biological Sciences (all)
Abstract :
[en] Sterile alpha motif domain-containing proteins 9 and 9-like (SAMD9/9L) are associated with life-threatening genetic diseases in humans and are restriction factors of poxviruses. Yet, their cellular function and the extent of their antiviral role are poorly known. Here, we found that interferon-stimulated human SAMD9L restricts HIV-1 in the late phases of replication, at the posttranscriptional and prematuration steps, impacting viral translation and, possibly, endosomal trafficking. Surprisingly, the paralog SAMD9 exerted an opposite effect, enhancing HIV-1. More broadly, we showed that SAMD9L restricts primate lentiviruses, but not a gammaretrovirus (MLV), nor 2 RNA viruses (arenavirus MOPV and rhabdovirus VSV). Using structural modeling and mutagenesis of SAMD9L, we identified a conserved Schlafen-like active site necessary for HIV-1 restriction by human and a rodent SAMD9L. By testing a gain-of-function constitutively active variant from patients with SAMD9L-associated autoinflammatory disease, we determined that SAMD9L pathogenic functions also depend on the Schlafen-like active site. Finally, we found that the constitutively active SAMD9L strongly inhibited HIV, MLV, and, to a lesser extent, MOPV. This suggests that the virus-specific effect of SAMD9L may involve its differential activation/sensing and the virus ability to evade from SAMD9L restriction. Overall, our study identifies SAMD9L as an HIV-1 antiviral factor from the cell autonomous immunity and deciphers host determinants underlying the translational repression. This provides novel links and therapeutic avenues against viral infections and genetic diseases.
Disciplines :
Microbiology
Author, co-author :
Legrand, Alexandre; Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, UCBL1, CNRS UMR 5308, ENS de Lyon, Université de Lyon, Lyon, France
Dahoui, Clara; Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, UCBL1, CNRS UMR 5308, ENS de Lyon, Université de Lyon, Lyon, France
de la Myre Mory, Clément ; Université de Liège - ULiège > Département de gestion vétérinaire des Ressources Animales (DRA) > Génomique animale ; Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, UCBL1, CNRS UMR 5308, ENS de Lyon, Université de Lyon, Lyon, France
Noy, Kodie; Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, UCBL1, CNRS UMR 5308, ENS de Lyon, Université de Lyon, Lyon, France ; Unité de Biologie des Infections Virales Émergentes, Institut Pasteur, Lyon, Université Paris Cité, Paris, France
Guiguettaz, Laura; Laboratoire de Biologie et Modélisation de la Cellule (LBMC), Université de Lyon, INSERM U1293, CNRS UMR 5239, ENS de Lyon, UCBL1, Lyon, France
Versapuech, Margaux; Université Paris Cité, CNRS, Inserm, Institut Cochin, INSERM, CNRS, Paris, France
Loyer, Clara; Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, UCBL1, CNRS UMR 5308, ENS de Lyon, Université de Lyon, Lyon, France
Pillon, Margaux; Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, UCBL1, CNRS UMR 5308, ENS de Lyon, Université de Lyon, Lyon, France
Wcislo, Mégane; Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, UCBL1, CNRS UMR 5308, ENS de Lyon, Université de Lyon, Lyon, France
Guéguen, Laurent; Laboratoire de Biologie et Biométrie Évolutive (LBBE), CNRS UMR 5558, UCBL1, Villeurbanne, France
Berlioz-Torrent, Clarisse; Université Paris Cité, CNRS, Inserm, Institut Cochin, INSERM, CNRS, Paris, France
Cimarelli, Andrea; Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, UCBL1, CNRS UMR 5308, ENS de Lyon, Université de Lyon, Lyon, France
Mateo, Mathieu; Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, UCBL1, CNRS UMR 5308, ENS de Lyon, Université de Lyon, Lyon, France ; Unité de Biologie des Infections Virales Émergentes, Institut Pasteur, Lyon, Université Paris Cité, Paris, France
Fiorini, Francesca; Retroviruses and structural biochemistry, Molecular Microbiology and Structural Biochemistry (MMSB), IBCP, CNRS UMR 5086, University of Lyon, Lyon, France
Ricci, Emiliano P; Laboratoire de Biologie et Modélisation de la Cellule (LBMC), Université de Lyon, INSERM U1293, CNRS UMR 5239, ENS de Lyon, UCBL1, Lyon, France
Etienne, Lucie ; Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, UCBL1, CNRS UMR 5308, ENS de Lyon, Université de Lyon, Lyon, France
amfAR - American Foundation for AIDS Research FRM - Fondation pour la Recherche Médicale FINOVI - Fondation Innovations en Infectiologie Sidaction CNRS - Centre National de la Recherche Scientifique UCBL - Université Claude Bernard. Lyon 1
Funding text :
Funding: This work was funded by grants from the French Research Agency on HIV and Emerging Infectious Diseases ANRS/MIE (#ECTZ19143 and #ECTZ118944 to LE, #ECTZ245897 to LE and FF, #ECTZ243795 to CBT, #ECTZ3306 to EPR), as well as from the ANR LABEX ECOFECT (ANR-11-LABX-0048 of Universit\u00E9 de Lyon, within the program \"Investissements d\u2019Avenir\" (ANR-11-IDEX-0007) operated by the French National Research Agency, to LE and LG), the amfAR (Mathilde Krim Phase II Fellowship #109140-58-RKHF, to LE), the \u201CFondation pour la Recherche M\u00E9dicale\u201D (FRM \u201CProjet Innovant\u201D #ING20160435028 to LE), the FINOVI (\u201Crecently settled scientist\u201D grant to LE), and the Sidaction (to LE #23-1-AEQ-13601, and to AC). LE and AC are supported by the CNRS. LG is supported by the Universit\u00E9 Claude Bernard Lyon 1 and Swedish Center of Advanced Study. AL is supported by PhD fellowships from Sidaction (2020 - n\u25E612673, 2023 - n\u25E613574). The funders play no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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