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

Lili Hu1,2, Renee M van der Sluis1,2, Kennith Brian Castelino1

  • 1Department of Biomedicine, Aarhus University, Aarhus, Denmark.

Nature Communications
|November 27, 2025
PubMed

Insights

Rare variants in RB1CC1, encoding FIP200 protein, are linked to critical COVID-19. FIP200 deficiency impairs a novel pathway that degrades SARS-CoV-2, independent of type I interferon.

Area of Science:

  • Virology
  • Immunology
  • Cell Biology

Background:

  • COVID-19 severity varies, with type I interferon deficiency implicated in severe cases.
  • RB1CC1 gene variants, encoding FIP200, were investigated in patients with critical COVID-19.

Purpose of the Study:

  • To investigate the role of FIP200 in SARS-CoV-2 infection and COVID-19 pathogenesis.
  • To identify the antiviral mechanisms involving FIP200.

Main Methods:

  • Analysis of patients with critical COVID-19 and RB1CC1 variants.
  • Genetic manipulation of FIP200 in airway epithelial cells and cell lines.
  • Assessment of SARS-CoV-2 replication and autophagic flux.
  • Investigation of FIP200's interaction with NDP52 and its role in viral degradation pathways.

Main Results:

  • Two unrelated male patients with critical COVID-19 had rare deleterious RB1CC1 variants.
  • FIP200-deficient cells and cells with patient variants showed increased SARS-CoV-2 replication and impaired autophagic flux.
  • FIP200 mediates SARS-CoV-2 degradation via a novel, non-canonical pathway involving NDP52 and lysosomal degradation, independent of canonical autophagy and type I IFN.

Conclusions:

  • A cell-autonomous antiviral pathway dependent on FIP200 and NDP52 restricts SARS-CoV-2.
  • This pathway, independent of canonical autophagy and type I IFN, targets virions for degradation in acidified vesicles.
  • Impairment of this FIP200-dependent pathway may contribute to critical COVID-19 pneumonia.

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