TY - JOUR
T1 - Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2
AU - COVID Human Genetic Effort
AU - Hu, Lili
AU - van der Sluis, Renee M.
AU - Castelino, Kennith Brian
AU - Zhang, Bao Cun
AU - Ronit, Andreas
AU - Zillinger, Thomas
AU - Werner, Marvin
AU - Jørgensen, Sofie Eg
AU - Hansen, Anne Louise
AU - Pedersen, Alice
AU - Narita, Ryo
AU - Reinert, Line S.
AU - Bundgaard, Bettina
AU - Helleberg, Marie
AU - Benfield, Thomas
AU - Storgaard, Merete
AU - Hansen, Kristoffer Skaalum
AU - Bodilsen, Jacob
AU - Zhang, Shen Ying
AU - Zhang, Qian
AU - Zatz, Mayana
AU - Wauters, Joost
AU - von Bernuth, Horst
AU - Vinh, Donald C.
AU - Vianna, Fernanda Sales Luiz
AU - van de Beek, Diederik
AU - Uddin, Mohammed J.
AU - Uddin, K. M.Furkan
AU - Turvey, Stuart E.
AU - Trouillet-Assant, Sophie
AU - Tiberghien, Pierre
AU - Thorball, Christian
AU - Temel, Şehime Gülsün
AU - Tayoun, Ahmad Abou
AU - Tangye, Stuart G.
AU - Tancevski, Ivan
AU - Su, Helen C.
AU - Spaan, András N.
AU - Soumelis, Vassili
AU - Soler-Palacín, Pere
AU - Snow, Andrew L.
AU - Slaby, Ondrej
AU - Shcherbina, Anna
AU - Shahrooei, Mohammad
AU - Seppänen, Mikko R.J.
AU - Sediva, Anna
AU - Sancho-Shimizu, Vanessa
AU - Rodríguez-Gallego, Carlos
AU - Resnick, Igor
AU - Perlin, David S.
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105023232059
U2 - 10.1038/s41467-025-65308-8
DO - 10.1038/s41467-025-65308-8
M3 - Article
C2 - 41309545
AN - SCOPUS:105023232059
SN - 2041-1723
VL - 16
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 10618
ER -