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

作者：Lili Hu, Renée M. van der Sluis, Kennith Brian Castelino, Bao‐cun Zhang, Andreas Ronit, Thomas Zillinger, Marvin Werner, Sofie E. Jørgensen, Anne Louise Hansen, Alice Pedersen, Ryo Narita, Line S. Reinert, Bettina Bundgaard, COVID Human Genetic Effort, Laurent Abel, Alessandro Aiuti, Saleh Al‐Muhsen, Fahd Al‐Mulla, Mark S. Anderson, Evangelos Andreakos, Andrés A. Arias, Lisa M. Arkin, Hagit Baris Feldman, Paul Bastard, Alexandre Belot, Catherine M. Biggs, Dusan Bogunovic, Alexandre Bolze, Анастасія Бондаренко, A. Borghesi, Ahmed Aziz Bousfiha, Petter Brodin, Yenan T. Bryceson, Giorgio Casari, John Christodoulou, Aurélie Cobat, Roger Colobrán, Antônio Condino‐Neto, Stefan N. Constantinescu, Megan A. Cooper, Clifton L. Dalgard, Murkesh Desai, Beth A. Drolet, Munis Dündar, Xavier Duval, Sotiriјa Duvlis, Jamila El Baghdadi, Philippine Eloy, Sara Elva Espinosa‐Padilla, Jacques Fellay, Carlos Flores, José Luis Franco, Antoine Froidure, Guy Gorochov, Marta Gut, Filomeen Haerynck, David Hagin, Rabih Halwani, Lennart Hammarström, James R. Heath, Elena W.Y. Hsieh, Eystein S. Husebye, Kohsuke Imai, Yuval Itan, Emmanuelle Jouanguy, Elżbieta Kaja, Timokratis Karamitros, Kai Kisand, Cheng‐Lung Ku, YL Lau, Yun Ling, C. Lucas, Matthieu Mahévas, Davood Mansouri, László Maródi, France Mentré, Isabelle Meyts, Joshua D. Milner, Kristina Mironska, Tomohiro Morio, Lisa F. P. Ng, L. D. Notarangelo, Antonio Novelli, Giuseppe Novelli, Cliona O’Farrelly, Satoshi Okada, Keisuke Okamoto, Tayfun Özçelık, Fırat Özçelik, Qiang Pan‐Hammarström, Rebeca Pérez de Diego, Jordi Pérez‐Tur, David S. Perlin, Jonny Peter, Anna M. Planas, Carolina Prando, Aurora Pujol, Anne Puel, Lluis Quintana-Murci, Sathishkumar Ramaswamy, Laurent Rénia, Igor Resnick, Carlos Rodríguez‐Gallego, Vanessa Sancho‐Shimizu, Anna Šedivá, Mikko Seppänen, Mohammad Shahrooei, Anna Shcherbina, Ondřej Slabý, Andrew L. Snow, Pere Soler‐Palacín, Vassili Soumelis, András N. Spaan, Helen C. Su, Ivan Tancevski, Stuart G. Tangye, Ahmad Abou Tayoun, Şehime Gülsün Temel, Christian W. Thorball, Pierre Tiberghien, Sophie Trouillet‐Assant, Stuart E. Turvey, K. M. Furkan Uddin, Mohammed Uddin, Diederik van de Beek, Fernanda Sales Luiz Vianna, Donald C. Vinh, Horst von Bernuth, Joost Wauters, Mayana Zatz, Qian Zhang, Shen‐Ying Zhang, Jacob Bodilsen, Kristoffer Skaalum Hansen, Merete Storgaard, Thomas Benfield, Marie Helleberg, Christian K. Holm, Aurélie Cobat, Jean‐Laurent Casanova, Fulvio Reggiori, Muriel Mari, Søren R. Paludan, Trine H. Mogensen · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-65308-8 · 被引用次数：3 · 研究领域：Autophagy in Disease and Therapy、interferon and immune responses、Endoplasmic Reticulum Stress and Disease

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. The variability in clinical outcomes of SARS-CoV-2 infection is partly due to deficiencies in production or response to type I interferons (IFN). Here, the authors describe a FIP200-dependent lysosomal degradation pathway, independent of canonical autophagy and t...