Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2

The clinical outcome of SARS-CoV-2 infection spans from asymptomatic viral elimination to lethal COVID-19 pneumonia, which is due to type I interferon (IFN) deficiency in at least 15-20% of cases. We report two unrelated male patients with critical COVID-19 who are heterozygous for rare deleterious variants in RB1CC1, encoding the autophagy-related FIP200 protein. Airway epithelial cells genetically deprived of FIP200 or cell lines expressing the RB1CC1/FIP200 patient variants exhibit elevated SARS-CoV-2 replication and impaired autophagic flux. The antiviral function of FIP200 is independent of canonical autophagy and type I IFN, but involves the selective autophagy receptor NDP52. We identify a non-canonical function of FIP200 in a novel lysosomal degradation pathway, in which SARS-CoV-2 virions are targeted to single-membrane compartments for degradation of viral RNA in LC3B-positive acidified vesicles. This pathway is impaired in FIP200-deficient cells and in cells expressing FIP200 patient haplotypes. Collectively, we describe a cell-autonomous anti-SARS-CoV-2 restriction pathway, dependent on FIP200 and NDP52, and independent of canonical autophagy and type I IFN, which can underlie critical COVID-19 pneumonia.

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Nature Communications
Published
2025-11-27
DOI
https://doi.org/10.1038/s41467-025-65308-8
Citations
1
Primary Topic
Autophagy in Disease and Therapy
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article
Field-Weighted Citation Impact
1.35

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article

Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2

Andreas Ronit, Filomeen Haerynck, Joshua D. Milner, Pere Soler‐Palacín et al.
1 citations
Nature Communications
Autophagy in Disease and Therapy
1.35
article

Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2

Andreas Ronit, Filomeen Haerynck, Joshua D. Milner, Pere Soler‐Palacín, Fulvio Reggiori, Sathishkumar Ramaswamy, Sotiriјa Duvlis, Andrew L. Snow, Evangelos Andreakos, Carolina Prando, Jonny Peter, Andrés A. Arias, Paul Bastard, Rebeca Pérez de Diego, Yun Ling, Bettina Bundgaard, Alice Pedersen, Antonio Novelli, Lisa F. P. Ng, Helen C. Su, Philippine Eloy, Yenan T. Bryceson, László Maródi, Marie Helleberg, Elena W.Y. Hsieh, Catherine M. Biggs, Horst von Bernuth, Tayfun Özçelık, David S. Perlin, Timokratis Karamitros, Fernanda Sales Luiz Vianna, Yuval Itan, Sophie Trouillet‐Assant, Muriel Mari, Anna Šedivá, Renée Marije van der Sluis, Lisa M. Arkin, Line S. Reinert, Carlos Rodríguez‐Gallego, Vanessa Sancho‐Shimizu, Sofie E. Jørgensen, Pierre Tiberghien, Satoshi Okada, France Mentré, Aurélie Cobat, Anne Louise Hansen, Stefan N. Constantinescu, Christian K. Holm, Antoine Froidure, Matthieu Mahévas, Isabelle Meyts, Tomohiro Morio, Stuart E. Turvey, Rabih Halwani, Sara Elva Espinosa‐Padilla, Elżbieta Kaja, Ivan Tancevski, Alexandre Bolze, Fahd Al‐Mulla, John Christodoulou, Laurent Marsollier, Bao‐cun Zhang, Jean‐Laurent Casanova, YL Lau, Munis Dündar, Murkesh Desai, Kristina Mironska, David Hagin, Ahmad Abou Tayoun, Joost Wauters, Ahmed Aziz Bousfiha, Alessandro Aiuti, Trine Hyrup Mogensen, Megan A. Cooper, Roger Colobrán, Eystein S. Husebye, Qiang Pan‐Hammarström, Anne Puel, Anna Shcherbina, Emmanuelle Jouanguy, C. Lucas, José Luis Franco, Thomas Zillinger, Beth A. Drolet, Marvin Werner, Анастасія Бондаренко, Şehime Gülsün Temel, Jamila El Baghdadi, Fırat Özçelik, K. M. Furkan Uddin, Jordi Pérez‐Tur, Mayana Zatz, Shen‐Ying Zhang, Laurent Rénia, Christian Wandall Thorball, Anna M. Planas, Petter Brodin, Alessandro Borghesi, Merete Storgaard, Søren R. Paludan, Giorgio Casari, Mikko Seppänen, Mohammad Shahrooei, Ryo Narita, Kristoffer Skaalum Hansen, Thomas Benfield, Kai Kisand, Giuseppe Novelli, Jacques Fellay, Jacob Bodilsen, Donald C. Vinh, Cheng‐Lung Ku, Antônio Condino‐Neto, Mark Stuart Anderson, Cliona O’Farrelly, Qian Zhang, Keisuke Okamoto, Kohsuke Imai, Lili Hu, Mohammed Uddin, Igor Resnick, Stuart G. Tangye, Guy Gorochov, James R. Heath, Lluis Quintana-Murci, Xavier Duval, Davood Mansouri, Clifton L. Dalgard, Hagit Baris Feldman, Carlos Flores, Alexandre Belot, Saleh Al‐Muhsen, Lennart Hammarström, Vassili Soumelis, Aurora Pujol, András N. Spaan, L. D. Notarangelo, Diederik van de Beek, Ondřej Slabý, Kennith Brian Castelino
article en
1 citations

Abstract

The clinical outcome of SARS-CoV-2 infection spans from asymptomatic viral elimination to lethal COVID-19 pneumonia, which is due to type I interferon (IFN) deficiency in at least 15-20% of cases. We report two unrelated male patients with critical COVID-19 who are heterozygous for rare deleterious variants in RB1CC1, encoding the autophagy-related FIP200 protein. Airway epithelial cells genetically deprived of FIP200 or cell lines expressing the RB1CC1/FIP200 patient variants exhibit elevated SARS-CoV-2 replication and impaired autophagic flux. The antiviral function of FIP200 is independent of canonical autophagy and type I IFN, but involves the selective autophagy receptor NDP52. We identify a non-canonical function of FIP200 in a novel lysosomal degradation pathway, in which SARS-CoV-2 virions are targeted to single-membrane compartments for degradation of viral RNA in LC3B-positive acidified vesicles. This pathway is impaired in FIP200-deficient cells and in cells expressing FIP200 patient haplotypes. Collectively, we describe a cell-autonomous anti-SARS-CoV-2 restriction pathway, dependent on FIP200 and NDP52, and independent of canonical autophagy and type I IFN, which can underlie critical COVID-19 pneumonia.

Nature CommunicationsVol. 16(1)
Université Claude Bernard Lyon 1 (FR), Semmelweis University (HU), Délégation Paris 5 (FR), Hiroshima University (JP), University of Geneva (CH), Agency for Science, Technology and Research (SG), University of Rome Tor Vergata (IT), Institució Catalana de Recerca i Estudis Avançats (ES), Universidad de Las Palmas de Gran Canaria (ES), Poznan University of Medical Sciences (PL), Centre National de la Recherche Scientifique (FR), National Institutes of Health (US), Universidade Federal do Rio Grande do Sul (BR), PepsiCo (United Kingdom) (GB), Central European Institute of Technology (CZ), Cliniques Universitaires Saint-Luc (BE), Bursa Uludağ Üni̇versi̇tesi̇ (TR), University of Helsinki (FI), Howard Hughes Medical Institute (US), University of Wisconsin–Madison (US), Garvan Institute of Medical Research (AU), Chang Gung University of Science and Technology (TW), University of British Columbia (CA), Innsbruck Medical University (AT), Uniformed Services University of the Health Sciences (US), Vita-Salute San Raffaele University (IT), Inserm (FR), Institut Pasteur (FR), University of Cape Town (ZA), The University of Melbourne (AU), Bilkent University (TR), Nanyang Technological University (SG), Chang Gung University (TW), Chinese University of Hong Kong (HK), Universidade de São Paulo (BR), University of California, San Francisco (US), Collège de France (FR), Universität Innsbruck (AT), Utrecht University (NL), Ludwig Cancer Research (BE), Université Paris-Est Créteil (FR), Aarhus University (DK), Washington University in St. Louis (US), Université Paris Cité (FR), Trinity College Dublin (IE), Academy of Athens (GR), Charles University (CZ), Columbia University Irving Medical Center (US), Tel Aviv Sourasky Medical Center (IL), Aalborg University Hospital (DK), Science for Life Laboratory (SE), Paris-Est Sup (FR), Helsinki University Hospital (FI), Haukeland University Hospital (NO), Al Jalila Foundation (AE), Ghent University Hospital (BE), Instituto de Salud Carlos III (ES), McGill University Health Centre (CA), Hvidovre Hospital (DK), King Saud University (SA), Groote Schuur Hospital (ZA), Aarhus University Hospital (DK), Copenhagen University Hospital (DK), Rigshospitalet (DK), Genome Canada (CA), Karolinska Institutet (SE), University of Sharjah (AE), University Medical Center Utrecht (NL), Masih Daneshvari Hospital (IR), Institute for Systems Biology (US), UNSW Sydney (AU), Yale University (US), Universidad de Antioquia (CO), Sorbonne Université (FR), Institut Necker Enfants Malades (FR), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Institut d'Investigació Biomédica de Bellvitge (ES), Hospital Universitario Nuestra Señora de Candelaria (ES), Central European Institute of Technology – Masaryk University (CZ), Universidad Fernando Pessoa Canarias (ES), Sorbonne Paris Cité (FR), Biomedical Research Foundation of the Academy of Athens (GR), University Hospital St. Marina (BG), Hospital de Clínicas de Porto Alegre (BR), Assistance Publique – Hôpitaux de Paris (FR), University Hospital in Motol (CZ), Hospital Universitario de Gran Canaria Doctor Negrín (ES), Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (ES), Hospices Civils de Lyon (FR), Instituto Tecnológico y de Energías Renovables (ES), Vall d'Hebron Institut de Recerca (ES), Hospital La Paz Institute for Health Research (ES), University Hospital of Geneva (CH), Shanghai Public Health Clinical Center (CN), Mohammed Bin Rashid University of Medicine and Health Sciences (AE), Amsterdam Neuroscience (NL), National Institute of Genomic Medicine (MX), Bai Jerbai Wadia Hospital for Children (IN), Centre for Biomedical Network Research on Rare Diseases (ES), de Duve Institute (BE), South African Tuberculosis Vaccine Initiative (ZA), Central European Institute of Technology (AT), Bambino Gesù Children's Hospital (IT), St Vincent's Clinic (AU), Pasteur Hellenic Institute (GR), Institut d'Investigacions Biomèdiques de Barcelona (ES), Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology (RU), Berlin-Brandenburger Centrum für Regenerative Therapien (DE), Vall d'Hebron Hospital Universitari (ES), Centre d'Immunologie et des Maladies Infectieuses (FR), Établissement Français du Sang (FR), European University (UA), National Institute of Allergy and Infectious Diseases (US), Institute of public health of Republic of Macedonia (MK), Stem Cell Institute (PA), Centre Hospitalier Universitaire Ibn Rochd (MA), Centro Nacional de Análisis Genómico (ES), The San Raffaele Telethon Institute for Gene Therapy (IT), Duran i Reynals Hospital (ES), St. Paul's Hospital (CA), Hôpital Saint-Louis (FR), Hôpital Bichat-Claude-Bernard (FR), The Health Care Science Institute (JP), Hackensack Meridian Health (US), Instituto de Biomedicina de Valencia (ES), Murdoch Children's Research Institute (AU), BC Children's Hospital (CA), Center for Discovery (US), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Goce Delcev University (MK), Tokyo Medical and Dental University Hospital (JP), Centre International de Recherche en Infectiologie (FR), Helix (United States) (US), Institut des Maladies Génétiques Imagine (FR), Dasman Diabetes Institute (KW), International European University, Holy Family Red Crescent Medical College, Institut de recherche Saint-Louis (FR), Imperial College London (GB), École Polytechnique Fédérale de Lausanne (CH), University of Colorado Anschutz Medical Campus (US), National Defense Medical College (JP), Royal College of Paediatrics and Child Health (GB), University of Tartu (EE), Shahid Beheshti University of Medical Sciences (IR), Geneva College (US), Universitat de Barcelona (ES), Ss. 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Fisher Center for Alzheimer's Research Foundation, St. Giles Foundation, Fondation du Souffle, Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation, Georgia Clinical and Translational Science Alliance, Institut des maladies génétiques Imagine, National Research Foundation, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Danmarks Grundforskningsfond, Fondation pour la Recherche Médicale, Lundbeckfonden, Novo Nordisk, Stavros Niarchos Foundation, Novo Nordisk Fonden, H. Lundbeck A/S, National Institutes of Health, HORIZON EUROPE Framework Programme, National Center for Advancing Translational Sciences, CHIST-ERA
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