Mutation T9I in Envelope confers autophagy resistance to SARS-CoV-2 Omicron

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...

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Published iniScience Vol. 28; no. 7; p. 112974
Main Authors Klute, Susanne, Nchioua, Rayhane, Cordsmeier, Arne, Vishwakarma, Jyoti, Koepke, Lennart, Alshammary, Hala, Jung, Christoph, Hirschenberger, Maximilian, Hoenigsperger, Helene, Fischer, Jana-Romana, Sivarajan, Rinu, Zech, Fabian, Stenger, Steffen, Serra-Moreno, Ruth, Gonzalez-Reiche, Ana Silvia, Sordillo, Emilia Mia, van Bakel, Harm, Simon, Viviana, Kirchhoff, Frank, Jacob, Timo, Kmiec, Dorota, Pichlmair, Andreas, Ensser, Armin, Sparrer, Konstantin Maria Johannes
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 18.07.2025
Elsevier
Subjects
Biological sciences
Cell biology
Microbiology
Natural sciences
Cell biology
Biological sciences
Natural sciences
Microbiology
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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. [Display omitted] •Omicron-associated E T9I renders incoming SARS-CoV-2 resistant to autophagy•T9I promotes interaction of E with autophagy-associated factors and autophagosomes•Autophagy evasion may have contributed to the effective spread of Omicron Natural sciences; Biological sciences; Microbiology; Cell biology
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ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2025.112974