%0 Journal Article %T Host succinate inhibits influenza virus infection through succinylation and nuclear retention of the viral nucleoprotein %+ Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR) %+ Centre Hospitalier Régional Universitaire de Tours (CHRU Tours) %+ Université de Tours (UT) %+ ERL 7001 LNOx (Leukemic Niche & redOx metabolism / Niche leucémique et métabolisme redOx) (LNOx) %+ Virologie et Immunologie Moléculaires (VIM (UR 0892)) %+ Novartis Institutes for BioMedical Research (NIBR) %+ Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ) %+ Institut Curie [Paris] %+ Laboratoire de Spectrométrie de Masse Protéomique %+ Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM) %+ Institut du Cancer de Montpellier (ICM) %+ Translational microbial Evolution and Engineering (TIMC-TrEE) %+ Centre Hospitalier Universitaire [Grenoble] (CHU) %+ IRMaGe (IRMaGe) %+ [GIN] Grenoble Institut des Neurosciences (GIN) %+ Institut de biologie structurale (IBS - UMR 5075) %+ Leiden University Medical Center (LUMC) %+ Biologie des ARN et virus influenza - RNA Biology of Influenza Virus (CNRS-UMR3569) %A Guillon, Antoine %A Bréa-Diakite, Deborah %A Cezard, Adeline %A Wacquiez, Alan %A Baranek, Thomas %A Bourgeais, Jérôme %A Picou, Frédéric %A Vasseur, Virginie %A Meyer, Léa %A Chevalier, Christophe %A Auvet, Adrien %A Carballido, José %A Desbarats, Lydie %A Dingli, Florent %A Turtoi, Andrei %A Le Gouellec, Audrey %A Fauvelle, Florence %A Donchet, Amélie %A Crepin, Thibaut %A Hiemstra, Pieter %A Paget, Christophe %A Loew, Damarys %A Herault, Olivier %A Naffakh, Nadia %A Le Goffic, Ronan %A Si-Tahar, Mustapha %Z This work was partially supported by the following grants: Inserm, Université of Tours, Région Centre-Val de Loire FLU-MET#2018-00124196, VLM#RF2018052289 (to M.S.-T.); FEDER Euro-FERI (to M.S.-T. and C.P.), Studium research fellowship (to P.S.H. and M.S.-T.), French research network on influenza viruses (ResaFlu, GDR2073) financed by CNRS (to M.S.-T, R.L.G, N.N., T.C., C.C.); SIRIC Montpellier Cancer Grant INCa_Inserm_DGOS_12553 (to A.T.); LabEx IBEID Grant No. 10-LABX-0062 (to N.N.); Ph.D. fellowship from INRAe – Department of animal health (to L.M.). This work used the platforms of the Grenoble Instruct-ERIC center (ISBG; UMS 3518 CNRS-CEA-UGA-EMBL) within the Grenoble Partnership for Structural Biology (PSB), supported by FRISBI (ANR-10-INBS-05-02) and GRAL, financed by the University Grenoble Alpes – Ecoles Universitaires de Recherche CBH-EUR-GS (ANR-17-EURE-0003). %< avec comité de lecture %@ 0261-4189 %J EMBO Journal %I EMBO Press %V 41 %N 12 %P e108306 %8 2022-06-14 %D 2022 %R 10.15252/embj.2021108306 %M 35506364 %K antiviral %K influenza %K metabokine %K signaling %K virus %Z Life Sciences [q-bio]/Human health and pathologyJournal articles %X Influenza virus infection causes considerable morbidity and mortality, but current therapies have limited efficacy. We hypothesized that investigating the metabolic signaling during infection may help to design innovative antiviral approaches. Using bronchoalveolar lavages of infected mice, we here demonstrate that influenza virus induces a major reprogramming of lung metabolism. We focused on mitochondria-derived succinate that accumulated both in the respiratory fluids of virus-challenged mice and of patients with influenza pneumonia. Notably, succinate displays a potent antiviral activity in vitro as it inhibits the multiplication of influenza A/H1N1 and A/H3N2 strains and strongly decreases virus-triggered metabolic perturbations and inflammatory responses. Moreover, mice receiving succinate intranasally showed reduced viral loads in lungs and increased survival compared to control animals. The antiviral mechanism involves a succinate-dependent posttranslational modification, that is, succinylation, of the viral nucleoprotein at the highly conserved K87 residue. Succinylation of viral nucleoprotein altered its electrostatic interactions with viral RNA and further impaired the trafficking of viral ribonucleoprotein complexes. The finding that succinate efficiently disrupts the influenza replication cycle opens up new avenues for improved treatment of influenza pneumonia. %G English %2 https://univ-tours.hal.science/hal-03687124v2/document %2 https://univ-tours.hal.science/hal-03687124v2/file/EMBJ-41-e108306%5B1%5D.pdf %L hal-03687124 %U https://univ-tours.hal.science/hal-03687124 %~ INSERM %~ PASTEUR %~ CEA %~ UGA %~ UNIV-TOURS %~ IMAG %~ CNRS %~ INPG %~ FNCLCC %~ VALDAURELLE %~ CURIE %~ TIMC-IMAG %~ IBS %~ UVSQ %~ IBS-VRM %~ CEA-UPSAY %~ PSL %~ UNIV-PARIS-SACLAY %~ UNIV-MONTPELLIER %~ CEA-DRF %~ IRCM %~ IRIG %~ CEA-GRE %~ UNIV-LYON %~ INRAE %~ UNIV-PARIS %~ UNIVERSITE-PARIS %~ VIM %~ INSTITUT-CURIE-PSL %~ UVSQ-UPSACLAY %~ UNIVERSITE-PARIS-SACLAY %~ UGA-EPE %~ ANR %~ GS-BIOSPHERA %~ GS-LIFE-SCIENCES-HEALTH %~ GS-HEALTH-DRUG-SCIENCES %~ TIMC-TREE %~ CEPR %~ UM-2015-2021 %~ UM-EPE %~ TEST3-HALCNRS %~ RNA-BIO-INF-VIR %~ PASTEUR_UMR3569 %~ SAPS