iScience (Jul 2025)
Mutation T9I in Envelope confers autophagy resistance to SARS-CoV-2 Omicron
- Susanne Klute,
- Rayhane Nchioua,
- Arne Cordsmeier,
- Jyoti Vishwakarma,
- Lennart Koepke,
- Hala Alshammary,
- Christoph Jung,
- Maximilian Hirschenberger,
- Helene Hoenigsperger,
- Jana-Romana Fischer,
- Rinu Sivarajan,
- Fabian Zech,
- Steffen Stenger,
- Ruth Serra-Moreno,
- Ana Silvia Gonzalez-Reiche,
- Emilia Mia Sordillo,
- Harm van Bakel,
- Viviana Simon,
- Frank Kirchhoff,
- Timo Jacob,
- Dorota Kmiec,
- Andreas Pichlmair,
- Armin Ensser,
- Konstantin Maria Johannes Sparrer
Affiliations
- Susanne Klute
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Baden-Württemberg, Germany
- Rayhane Nchioua
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Baden-Württemberg, Germany
- Arne Cordsmeier
- Institute for Clinical and Molecular Virology, University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Bavaria, Germany
- Jyoti Vishwakarma
- Institute of Virology, School of Medicine, Technical University of Munich, 80333 Munich, Bavaria, Germany
- Lennart Koepke
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Baden-Württemberg, Germany
- Hala Alshammary
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Baden-Württemberg, Germany; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Center for Vaccine Research and Pandemic Preparedness (C-VaRPP), Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Christoph Jung
- Institute of Electrochemistry, Ulm University, 89081 Ulm, Baden-Württemberg, Germany; Helmholtz-Institute Ulm (HIU) Electrochemical Energy Storage, 89081 Ulm, Baden-Württemberg, Germany; Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Baden-Württemberg, Germany
- Maximilian Hirschenberger
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Baden-Württemberg, Germany
- Helene Hoenigsperger
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Baden-Württemberg, Germany
- Jana-Romana Fischer
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Baden-Württemberg, Germany; German Center for Neurodegenerative Diseases (DZNE), 89081 Ulm, Baden-Württemberg, Germany
- Rinu Sivarajan
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Baden-Württemberg, Germany
- Fabian Zech
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Baden-Württemberg, Germany
- Steffen Stenger
- Institute of Medical Microbiology and Hygiene, Ulm University Medical Center, 89081 Ulm, Baden-Württemberg, Germany
- Ruth Serra-Moreno
- Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA
- Ana Silvia Gonzalez-Reiche
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Emilia Mia Sordillo
- Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Harm van Bakel
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Viviana Simon
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Center for Vaccine Research and Pandemic Preparedness (C-VaRPP), Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Frank Kirchhoff
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Baden-Württemberg, Germany
- Timo Jacob
- Institute of Electrochemistry, Ulm University, 89081 Ulm, Baden-Württemberg, Germany
- Dorota Kmiec
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Baden-Württemberg, Germany
- Andreas Pichlmair
- Institute of Virology, School of Medicine, Technical University of Munich, 80333 Munich, Bavaria, Germany
- Armin Ensser
- Institute for Clinical and Molecular Virology, University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Bavaria, Germany
- Konstantin Maria Johannes Sparrer
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Baden-Württemberg, Germany; German Center for Neurodegenerative Diseases (DZNE), 89081 Ulm, Baden-Württemberg, Germany; Corresponding author
- Journal volume & issue
-
Vol. 28,
no. 7
p. 112974
Abstract
Summary: Omicron has emerged as the most successful variant of SARS-CoV-2. In addition to mutations in Spike that mediate humoral immune escape, the Omicron-specific Envelope (E) T9I mutation has been associated with increased transmission fitness. However, the underlying mechanism remained unclear. Here, we demonstrate that the E T9I mutation confers resistance to autophagy. Rare Omicron patient isolates encoding the ancestral E T9 remain sensitive to autophagy. Conversely, introducing the E T9I mutation in recombinant 2020 SARS-CoV-2 renders it resistant to autophagy. Our data indicate that the E T9I mutation protects virions against lysosomal degradation. At the molecular level, the T9I mutation increases the localization of E at autophagic vesicles and promotes interaction with autophagy-associated proteins SNX12, STX12, TMEM87B, and ABCG2. Our results show that the E T9I mutation renders incoming virions resistant to autophagy, suggesting that evasion of this antiviral mechanism contributes to the efficient spread of Omicron.
