Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2
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HU, Lili; Renee M. VAN DER SLUIS; Kennith Brian CASTELINO; Bao-Cun ZHANG; Andreas RONIT; Thomas ZILLINGER; Marvin WERNER; Sofie Eg JORGENSEN; Anne Louise HANSEN; Alice PEDERSEN; Ryo NARITA; Line S. REINERT; Bettina BUNDGAARD; Laurent ABEL; Alessandro AIUTI; Saleh AL-MUHSEN; Fahd AL-MULLA; Mark S. ANDERSON; Evangelos ANDREAKOS; Andres A. ARIAS; Lisa M. ARKIN; Hagit Baris FELDMAN; Paul BASTARD; Alexandre BELOT; Catherine M. BIGGS; Dusan BOGUNOVIC; Alexandre BOLZE; Anastasiia BONDARENKO; Alessandro BORGHESI; Ahmed A. BOUSFIHA; Petter BRODIN; Yenan BRYCESON; Giorgio CASARI; John CHRISTODOULOU; Aurelie COBAT; Roger COLOBRAN; Antonio CONDINO-NETO; Stefan N. CONSTANTINESCU; Megan A. COOPER; Clifton L. DALGARD; Murkesh DESAI; Beth A. DROLET; Munis DUNDAR; Xavier DUVAL; Sotirija DUVLIS; Jamila EL BAGHDADI; Philippine ELOY; Sara ESPINOSA-PADILLA; Jacques FELLAY; Carlos FLORES; Jose Luis FRANCO; Antoine FROIDURE; Guy GOROCHOV; Marta GUT; Filomeen HAERYNCK; David HAGIN; Rabih HALWANI; Lennart HAMMARSTROM; James R. HEATH; Elena W. Y. HSIEH; Eystein HUSEBYE; Kohsuke IMAI; Yuval ITAN; Emmanuelle JOUANGUY; Elzbieta KAJA; Timokratis KARAMITROS; Kai KISAND; Cheng-Lung KU; Yu-Lung LAU; Ling YUN; Carrie L. LUCAS; Matthieu MAHEVAS; Davood MANSOURI; Laszlo MARODI; France MENTRE; Isabelle MEYTS; Joshua D. MILNER; Kristina MIRONSKA; Tomohiro MORIO; Lisa F. P. NG; Luigi D. NOTARANGELO; Antonio NOVELLI; Giuseppe NOVELLI; Cliona O'FARRELLY; Satoshi OKADA; Keisuke OKAMOTO; Tayfun OZCELIK; Firat OZCELIK; Qiang PAN-HAMMARSTROM; Rebeca DE DIEGO PEREZ; Jordi PEREZ-TUR; David S. PERLIN; Jonny PETER; Anna M. PLANAS; Carolina PRANDO; Aurora PUJOL; Anne PUEL; Lluis QUINTANA-MURCI; Sathishkumar RAMASWAMY; Laurent RENIA; Igor RESNICK; Carlos RODRIGUEZ-GALLEGO; Vanessa SANCHO-SHIMIZU; Anna SEDIVA; Mikko R. J. SEPPANEN; Mohammad SHAHROOEI; Anna SHCHERBINA; Ondřej SLABÝ; Andrew L. SNOW; Pere SOLER-PALACIN; Vassili SOUMELIS; Andras N. SPAAN; Helen C. SU; Ivan TANCEVSKI; Stuart G. TANGYE; Ahmad Abou TAYOUN; Sehime Gulsun TEMEL; Christian THORBALL; Pierre TIBERGHIEN; Sophie TROUILLET-ASSANT; Stuart E. TURVEY; K. M. Furkan UDDIN; Mohammed J. 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; Aurelie COBAT; Jean-Laurent CASANOVA; Fulvio REGGIORI; Muriel MARI; Soren R. PALUDAN a Trine H. MOGENSEN
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.
HU, Lili; Renee M. VAN DER SLUIS; Kennith Brian CASTELINO; Bao-Cun ZHANG; Andreas RONIT; Thomas ZILLINGER; Marvin WERNER; Sofie Eg JORGENSEN; Anne Louise HANSEN; Alice PEDERSEN; Ryo NARITA; Line S. REINERT; Bettina BUNDGAARD; Laurent ABEL; Alessandro AIUTI; Saleh AL-MUHSEN; Fahd AL-MULLA; Mark S. ANDERSON; Evangelos ANDREAKOS; Andres A. ARIAS; Lisa M. ARKIN; Hagit Baris FELDMAN; Paul BASTARD; Alexandre BELOT; Catherine M. BIGGS; Dusan BOGUNOVIC; Alexandre BOLZE; Anastasiia BONDARENKO; Alessandro BORGHESI; Ahmed A. BOUSFIHA; Petter BRODIN; Yenan BRYCESON; Giorgio CASARI; John CHRISTODOULOU; Aurelie COBAT; Roger COLOBRAN; Antonio CONDINO-NETO; Stefan N. CONSTANTINESCU; Megan A. COOPER; Clifton L. DALGARD; Murkesh DESAI; Beth A. DROLET; Munis DUNDAR; Xavier DUVAL; Sotirija DUVLIS; Jamila EL BAGHDADI; Philippine ELOY; Sara ESPINOSA-PADILLA; Jacques FELLAY; Carlos FLORES; Jose Luis FRANCO; Antoine FROIDURE; Guy GOROCHOV; Marta GUT; Filomeen HAERYNCK; David HAGIN; Rabih HALWANI; Lennart HAMMARSTROM; James R. HEATH; Elena W. Y. HSIEH; Eystein HUSEBYE; Kohsuke IMAI; Yuval ITAN; Emmanuelle JOUANGUY; Elzbieta KAJA; Timokratis KARAMITROS; Kai KISAND; Cheng-Lung KU; Yu-Lung LAU; Ling YUN; Carrie L. LUCAS; Matthieu MAHEVAS; Davood MANSOURI; Laszlo MARODI; France MENTRE; Isabelle MEYTS; Joshua D. MILNER; Kristina MIRONSKA; Tomohiro MORIO; Lisa F. P. NG; Luigi D. NOTARANGELO; Antonio NOVELLI; Giuseppe NOVELLI; Cliona O'FARRELLY; Satoshi OKADA; Keisuke OKAMOTO; Tayfun OZCELIK; Firat OZCELIK; Qiang PAN-HAMMARSTROM; Rebeca DE DIEGO PEREZ; Jordi PEREZ-TUR; David S. PERLIN; Jonny PETER; Anna M. PLANAS; Carolina PRANDO; Aurora PUJOL; Anne PUEL; Lluis QUINTANA-MURCI; Sathishkumar RAMASWAMY; Laurent RENIA; Igor RESNICK; Carlos RODRIGUEZ-GALLEGO; Vanessa SANCHO-SHIMIZU; Anna SEDIVA; Mikko R. J. SEPPANEN; Mohammad SHAHROOEI; Anna SHCHERBINA; Ondřej SLABÝ; Andrew L. SNOW; Pere SOLER-PALACIN; Vassili SOUMELIS; Andras N. SPAAN; Helen C. SU; Ivan TANCEVSKI; Stuart G. TANGYE; Ahmad Abou TAYOUN; Sehime Gulsun TEMEL; Christian THORBALL; Pierre TIBERGHIEN; Sophie TROUILLET-ASSANT; Stuart E. TURVEY; K. M. Furkan UDDIN; Mohammed J. 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; Aurelie COBAT; Jean-Laurent CASANOVA; Fulvio REGGIORI; Muriel MARI; Soren R. PALUDAN a Trine H. MOGENSEN. Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2. Nature communications. BERLIN: NATURE PORTFOLIO, 2025, roč. 16, č. 1, s. 1-23. ISSN 2041-1723. Dostupné z: https://doi.org/10.1038/s41467-025-65308-8.
@article{2544169, author = {Hu, Lili and Van der Sluis, Renee M. and Castelino, Kennith Brian and Zhang, BaoandCun and Ronit, Andreas and Zillinger, Thomas and Werner, Marvin and Jorgensen, Sofie Eg and Hansen, Anne Louise and Pedersen, Alice and Narita, Ryo and Reinert, Line S. and Bundgaard, Bettina and Abel, Laurent and Aiuti, Alessandro and AlandMuhsen, Saleh and AlandMulla, Fahd and Anderson, Mark S. and Andreakos, Evangelos and Arias, Andres A. and Arkin, Lisa M. and Feldman, Hagit Baris and Bastard, Paul and Belot, Alexandre and Biggs, Catherine M. and Bogunovic, Dusan and Bolze, Alexandre and Bondarenko, Anastasiia and Borghesi, Alessandro and Bousfiha, Ahmed A. and Brodin, Petter and Bryceson, Yenan and Casari, Giorgio and Christodoulou, John and Cobat, Aurelie and Colobran, Roger and CondinoandNeto, Antonio and Constantinescu, Stefan N. and Cooper, Megan A. and Dalgard, Clifton L. and Desai, Murkesh and Drolet, Beth A. and Dundar, Munis and Duval, Xavier and Duvlis, Sotirija and El Baghdadi, Jamila and Eloy, Philippine and EspinosaandPadilla, Sara and Fellay, Jacques and Flores, Carlos and Franco, Jose Luis and Froidure, Antoine and Gorochov, Guy and Gut, Marta and Haerynck, Filomeen and Hagin, David and Halwani, Rabih and Hammarstrom, Lennart and Heath, James R. and Hsieh, Elena W. Y. and Husebye, Eystein and Imai, Kohsuke and Itan, Yuval and Jouanguy, Emmanuelle and Kaja, Elzbieta and Karamitros, Timokratis and Kisand, Kai and Ku, ChengandLung and Lau, YuandLung and Yun, Ling and Lucas, Carrie L. and Mahevas, Matthieu and Mansouri, Davood and Marodi, Laszlo and Mentre, France and Meyts, Isabelle and Milner, Joshua D. and Mironska, Kristina and Morio, Tomohiro and Ng, Lisa F. P. and Notarangelo, Luigi D. and Novelli, Antonio and Novelli, Giuseppe and O'farrelly, Cliona and Okada, Satoshi and Okamoto, Keisuke and Ozcelik, Tayfun and Ozcelik, Firat and PanandHammarstrom, Qiang and De Diego Perez, Rebeca and PerezandTur, Jordi and Perlin, David S. and Peter, Jonny and Planas, Anna M. and Prando, Carolina and Pujol, Aurora and Puel, Anne and QuintanaandMurci, Lluis and Ramaswamy, Sathishkumar and Renia, Laurent and Resnick, Igor and RodriguezandGallego, Carlos and SanchoandShimizu, Vanessa and Sediva, Anna and Seppanen, Mikko R. J. and Shahrooei, Mohammad and Shcherbina, Anna and Slabý, Ondřej and Snow, Andrew L. and SolerandPalacin, Pere and Soumelis, Vassili and Spaan, Andras N. and Su, Helen C. and Tancevski, Ivan and Tangye, Stuart G. and Tayoun, Ahmad Abou and Temel, Sehime Gulsun and Thorball, Christian and Tiberghien, Pierre and TrouilletandAssant, Sophie and Turvey, Stuart E. and Uddin, K. M. Furkan and Uddin, Mohammed J. and Van De Beek, Diederik and Vianna, Fernanda Sales Luiz and Vinh, Donald C. and Von Bernuth, Horst and Wauters, Joost and Zatz, Mayana and Zhang, Qian and Zhang, ShenandYing and Bodilsen, Jacob and Hansen, Kristoffer Skaalum and Storgaard, Merete and Benfield, Thomas and Helleberg, Marie and Holm, Christian K. and Cobat, Aurelie and Casanova, JeanandLaurent and Reggiori, Fulvio and Mari, Muriel and Paludan, Soren R. and Mogensen, Trine H.}, article_location = {BERLIN}, article_number = {1}, doi = {https://doi.org/10.1038/s41467-025-65308-8}, keywords = {ENDOPLASMIC-RETICULUM TURNOVER; INDEPENDENT FUNCTIONS; VIRUS-INFECTION; RECEPTOR; PROTEINS; PATHWAY}, language = {eng}, issn = {2041-1723}, journal = {Nature communications}, title = {Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2}, url = {https://www.nature.com/articles/s41467-025-65308-8}, volume = {16}, year = {2025} }
TY - JOUR ID - 2544169 AU - Hu, Lili - Van der Sluis, Renee M. - Castelino, Kennith Brian - Zhang, Bao-Cun - Ronit, Andreas - Zillinger, Thomas - Werner, Marvin - Jorgensen, Sofie Eg - Hansen, Anne Louise - Pedersen, Alice - Narita, Ryo - Reinert, Line S. - Bundgaard, Bettina - Abel, Laurent - Aiuti, Alessandro - Al-Muhsen, Saleh - Al-Mulla, Fahd - Anderson, Mark S. - Andreakos, Evangelos - Arias, Andres A. - Arkin, Lisa M. - Feldman, Hagit Baris - Bastard, Paul - Belot, Alexandre - Biggs, Catherine M. - Bogunovic, Dusan - Bolze, Alexandre - Bondarenko, Anastasiia - Borghesi, Alessandro - Bousfiha, Ahmed A. - Brodin, Petter - Bryceson, Yenan - Casari, Giorgio - Christodoulou, John - Cobat, Aurelie - Colobran, Roger - Condino-Neto, Antonio - Constantinescu, Stefan N. - Cooper, Megan A. - Dalgard, Clifton L. - Desai, Murkesh - Drolet, Beth A. - Dundar, Munis - Duval, Xavier - Duvlis, Sotirija - El Baghdadi, Jamila - Eloy, Philippine - Espinosa-Padilla, Sara - Fellay, Jacques - Flores, Carlos - Franco, Jose Luis - Froidure, Antoine - Gorochov, Guy - Gut, Marta - Haerynck, Filomeen - Hagin, David - Halwani, Rabih - Hammarstrom, Lennart - Heath, James R. - Hsieh, Elena W. Y. - Husebye, Eystein - Imai, Kohsuke - Itan, Yuval - Jouanguy, Emmanuelle - Kaja, Elzbieta - Karamitros, Timokratis - Kisand, Kai - Ku, Cheng-Lung - Lau, Yu-Lung - Yun, Ling - Lucas, Carrie L. - Mahevas, Matthieu - Mansouri, Davood - Marodi, Laszlo - Mentre, France - Meyts, Isabelle - Milner, Joshua D. - Mironska, Kristina - Morio, Tomohiro - Ng, Lisa F. P. - Notarangelo, Luigi D. - Novelli, Antonio - Novelli, Giuseppe - O'farrelly, Cliona - Okada, Satoshi - Okamoto, Keisuke - Ozcelik, Tayfun - Ozcelik, Firat - Pan-Hammarstrom, Qiang - De Diego Perez, Rebeca - Perez-Tur, Jordi - Perlin, David S. - Peter, Jonny - Planas, Anna M. - Prando, Carolina - Pujol, Aurora - Puel, Anne - Quintana-Murci, Lluis - Ramaswamy, Sathishkumar - Renia, Laurent - Resnick, Igor - Rodriguez-Gallego, Carlos - Sancho-Shimizu, Vanessa - Sediva, Anna - Seppanen, Mikko R. J. - Shahrooei, Mohammad - Shcherbina, Anna - Slabý, Ondřej - Snow, Andrew L. - Soler-Palacin, Pere - Soumelis, Vassili - Spaan, Andras N. - Su, Helen C. - Tancevski, Ivan - Tangye, Stuart G. - Tayoun, Ahmad Abou - Temel, Sehime Gulsun - Thorball, Christian - Tiberghien, Pierre - Trouillet-Assant, Sophie - Turvey, Stuart E. - Uddin, K. M. Furkan - Uddin, Mohammed J. - Van De Beek, Diederik - Vianna, Fernanda Sales Luiz - Vinh, Donald C. - Von Bernuth, Horst - Wauters, Joost - Zatz, Mayana - Zhang, Qian - Zhang, Shen-Ying - Bodilsen, Jacob - Hansen, Kristoffer Skaalum - Storgaard, Merete - Benfield, Thomas - Helleberg, Marie - Holm, Christian K. - Cobat, Aurelie - Casanova, Jean-Laurent - Reggiori, Fulvio - Mari, Muriel - Paludan, Soren R. - Mogensen, Trine H. PY - 2025 TI - Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2 JF - Nature communications VL - 16 IS - 1 SP - 1-23 EP - 1-23 PB - NATURE PORTFOLIO SN - 20411723 KW - ENDOPLASMIC-RETICULUM TURNOVER KW - INDEPENDENT FUNCTIONS KW - VIRUS-INFECTION KW - RECEPTOR KW - PROTEINS KW - PATHWAY UR - https://www.nature.com/articles/s41467-025-65308-8 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. ER -
HU, Lili; Renee M. VAN DER SLUIS; Kennith Brian CASTELINO; Bao-Cun ZHANG; Andreas RONIT; Thomas ZILLINGER; Marvin WERNER; Sofie Eg JORGENSEN; Anne Louise HANSEN; Alice PEDERSEN; Ryo NARITA; Line S. REINERT; Bettina BUNDGAARD; Laurent ABEL; Alessandro AIUTI; Saleh AL-MUHSEN; Fahd AL-MULLA; Mark S. ANDERSON; Evangelos ANDREAKOS; Andres A. ARIAS; Lisa M. ARKIN; Hagit Baris FELDMAN; Paul BASTARD; Alexandre BELOT; Catherine M. BIGGS; Dusan BOGUNOVIC; Alexandre BOLZE; Anastasiia BONDARENKO; Alessandro BORGHESI; Ahmed A. BOUSFIHA; Petter BRODIN; Yenan BRYCESON; Giorgio CASARI; John CHRISTODOULOU; Aurelie COBAT; Roger COLOBRAN; Antonio CONDINO-NETO; Stefan N. CONSTANTINESCU; Megan A. COOPER; Clifton L. DALGARD; Murkesh DESAI; Beth A. DROLET; Munis DUNDAR; Xavier DUVAL; Sotirija DUVLIS; Jamila EL BAGHDADI; Philippine ELOY; Sara ESPINOSA-PADILLA; Jacques FELLAY; Carlos FLORES; Jose Luis FRANCO; Antoine FROIDURE; Guy GOROCHOV; Marta GUT; Filomeen HAERYNCK; David HAGIN; Rabih HALWANI; Lennart HAMMARSTROM; James R. HEATH; Elena W. Y. HSIEH; Eystein HUSEBYE; Kohsuke IMAI; Yuval ITAN; Emmanuelle JOUANGUY; Elzbieta KAJA; Timokratis KARAMITROS; Kai KISAND; Cheng-Lung KU; Yu-Lung LAU; Ling YUN; Carrie L. LUCAS; Matthieu MAHEVAS; Davood MANSOURI; Laszlo MARODI; France MENTRE; Isabelle MEYTS; Joshua D. MILNER; Kristina MIRONSKA; Tomohiro MORIO; Lisa F. P. NG; Luigi D. NOTARANGELO; Antonio NOVELLI; Giuseppe NOVELLI; Cliona O'FARRELLY; Satoshi OKADA; Keisuke OKAMOTO; Tayfun OZCELIK; Firat OZCELIK; Qiang PAN-HAMMARSTROM; Rebeca DE DIEGO PEREZ; Jordi PEREZ-TUR; David S. PERLIN; Jonny PETER; Anna M. PLANAS; Carolina PRANDO; Aurora PUJOL; Anne PUEL; Lluis QUINTANA-MURCI; Sathishkumar RAMASWAMY; Laurent RENIA; Igor RESNICK; Carlos RODRIGUEZ-GALLEGO; Vanessa SANCHO-SHIMIZU; Anna SEDIVA; Mikko R. J. SEPPANEN; Mohammad SHAHROOEI; Anna SHCHERBINA; Ondřej SLABÝ; Andrew L. SNOW; Pere SOLER-PALACIN; Vassili SOUMELIS; Andras N. SPAAN; Helen C. SU; Ivan TANCEVSKI; Stuart G. TANGYE; Ahmad Abou TAYOUN; Sehime Gulsun TEMEL; Christian THORBALL; Pierre TIBERGHIEN; Sophie TROUILLET-ASSANT; Stuart E. TURVEY; K. M. Furkan UDDIN; Mohammed J. 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; Aurelie COBAT; Jean-Laurent CASANOVA; Fulvio REGGIORI; Muriel MARI; Soren R. PALUDAN a Trine H. MOGENSEN. Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2. \textit{Nature communications}. BERLIN: NATURE PORTFOLIO, 2025, roč.~16, č.~1, s.~1-23. ISSN~2041-1723. Dostupné z: https://doi.org/10.1038/s41467-025-65308-8.