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...

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Detalles Bibliográficos
Autores: Hu, Lili, Covid Human Genetic Effort Group, Gut, Marta, Planas Obradors, Anna Maria, Pujol, Aurora, Solar Palacin, Pere, Mogensen, Trine H.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/226907
Acceso en línea:https://hdl.handle.net/2445/226907
Access Level:acceso abierto
Palabra clave:SARS-CoV-2
Síndromes de deficiència immunitària
Malalties hereditàries
Immunological deficiency syndromes
Genetic diseases
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spelling Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2Hu, LiliCovid Human Genetic Effort GroupGut, MartaPlanas Obradors, Anna MariaPujol, AuroraSolar Palacin, PereMogensen, Trine H.SARS-CoV-2Síndromes de deficiència immunitàriaMalalties hereditàriesSARS-CoV-2Immunological deficiency syndromesGenetic diseasesThe 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.Springer Science and Business Media LLC2026202620252026info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion23 p.application/pdfhttps://hdl.handle.net/2445/226907Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1038/s41467-025-65308-8Nature Communications, 2025, vol. 16, 10618https://doi.org/10.1038/s41467-025-65308-8cc-by-nc-nd (c) Hu, Lili et al., 2025https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/2269072026-05-29T05:05:01Z
dc.title.none.fl_str_mv Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2
title Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2
spellingShingle Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2
Hu, Lili
SARS-CoV-2
Síndromes de deficiència immunitària
Malalties hereditàries
SARS-CoV-2
Immunological deficiency syndromes
Genetic diseases
title_short Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2
title_full Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2
title_fullStr Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2
title_full_unstemmed Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2
title_sort Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2
dc.creator.none.fl_str_mv Hu, Lili
Covid Human Genetic Effort Group
Gut, Marta
Planas Obradors, Anna Maria
Pujol, Aurora
Solar Palacin, Pere
Mogensen, Trine H.
author Hu, Lili
author_facet Hu, Lili
Covid Human Genetic Effort Group
Gut, Marta
Planas Obradors, Anna Maria
Pujol, Aurora
Solar Palacin, Pere
Mogensen, Trine H.
author_role author
author2 Covid Human Genetic Effort Group
Gut, Marta
Planas Obradors, Anna Maria
Pujol, Aurora
Solar Palacin, Pere
Mogensen, Trine H.
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv SARS-CoV-2
Síndromes de deficiència immunitària
Malalties hereditàries
SARS-CoV-2
Immunological deficiency syndromes
Genetic diseases
topic SARS-CoV-2
Síndromes de deficiència immunitària
Malalties hereditàries
SARS-CoV-2
Immunological deficiency syndromes
Genetic diseases
description 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.
publishDate 2025
dc.date.none.fl_str_mv 2025
2026
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/226907
url https://hdl.handle.net/2445/226907
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/s41467-025-65308-8
Nature Communications, 2025, vol. 16, 10618
https://doi.org/10.1038/s41467-025-65308-8
dc.rights.none.fl_str_mv cc-by-nc-nd (c) Hu, Lili et al., 2025
https://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) Hu, Lili et al., 2025
https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 23 p.
application/pdf
dc.publisher.none.fl_str_mv Springer Science and Business Media LLC
publisher.none.fl_str_mv Springer Science and Business Media LLC
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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