tetano
Editor, Senior Moderator
Nat Commun
. 2025 Nov 27;16(1):10618.
doi: 10.1038/s41467-025-65308-8. Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2
Lili Hu[SUP] 1 2 [/SUP], Renee M van der Sluis[SUP] #[/SUP][SUP] 1 2 [/SUP], Kennith Brian Castelino[SUP] #[/SUP][SUP] 1 [/SUP], Bao-Cun Zhang[SUP] 1 2 [/SUP], Andreas Ronit[SUP] 3 [/SUP], Thomas Zillinger[SUP] 1 2 [/SUP], Marvin Werner[SUP] 1 2 [/SUP], Sofie Eg Jørgensen[SUP] 1 2 [/SUP], Anne Louise Hansen[SUP] 1 [/SUP], Alice Pedersen[SUP] 1 [/SUP], Ryo Narita[SUP] 1 2 [/SUP], Line S Reinert[SUP] 1 2 [/SUP], Bettina Bundgaard[SUP] 1 2 [/SUP]; COVID Human Genetic Effort; Christian K Holm[SUP] 1 [/SUP], Aurelie Cobat[SUP] 4 5 6 [/SUP], Jean-Laurent Casanova[SUP] 4 5 6 7 8 [/SUP], Fulvio Reggiori[SUP] #[/SUP][SUP] 1 [/SUP], Muriel Mari[SUP] #[/SUP][SUP] 1 [/SUP], Søren R Paludan[SUP] 1 2 [/SUP], Trine H Mogensen[SUP] 9 10 11 [/SUP]
Collaborators, Affiliations
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.
. 2025 Nov 27;16(1):10618.
doi: 10.1038/s41467-025-65308-8. Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2
Lili Hu[SUP] 1 2 [/SUP], Renee M van der Sluis[SUP] #[/SUP][SUP] 1 2 [/SUP], Kennith Brian Castelino[SUP] #[/SUP][SUP] 1 [/SUP], Bao-Cun Zhang[SUP] 1 2 [/SUP], Andreas Ronit[SUP] 3 [/SUP], Thomas Zillinger[SUP] 1 2 [/SUP], Marvin Werner[SUP] 1 2 [/SUP], Sofie Eg Jørgensen[SUP] 1 2 [/SUP], Anne Louise Hansen[SUP] 1 [/SUP], Alice Pedersen[SUP] 1 [/SUP], Ryo Narita[SUP] 1 2 [/SUP], Line S Reinert[SUP] 1 2 [/SUP], Bettina Bundgaard[SUP] 1 2 [/SUP]; COVID Human Genetic Effort; Christian K Holm[SUP] 1 [/SUP], Aurelie Cobat[SUP] 4 5 6 [/SUP], Jean-Laurent Casanova[SUP] 4 5 6 7 8 [/SUP], Fulvio Reggiori[SUP] #[/SUP][SUP] 1 [/SUP], Muriel Mari[SUP] #[/SUP][SUP] 1 [/SUP], Søren R Paludan[SUP] 1 2 [/SUP], Trine H Mogensen[SUP] 9 10 11 [/SUP]
Collaborators, Affiliations
- PMID: 41309545
- DOI: 10.1038/s41467-025-65308-8
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.