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

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Hu L, van der Sluis RM, Castelino KB, Zhang BC, Ronit A, Zillinger T, Werner M, Jørgensen SE, Hansen AL, Pedersen A, Narita R, Reinert LS, Bundgaard B, COVID Human Genetic Effort , Holm CK, Cobat A, Casanova JL, Reggiori F, Mari M, Paludan SR, Mogensen TH

Nat Commun 16 (1) 10618 [2025-11-27; online 2025-11-27]

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.

PubMed 41309545

DOI 10.1038/s41467-025-65308-8

Crossref 10.1038/s41467-025-65308-8

pmc: PMC12660716
pii: 10.1038/s41467-025-65308-8