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

Klute S, Nchioua R, Cordsmeier A, Vishwakarma J, Koepke L, Alshammary H, Jung C, Hirschenberger M, Hoenigsperger H, Fischer JR, Sivarajan R, Zech F, Stenger S, Serra-Moreno R, Gonzalez-Reiche AS, Sordillo EM, van Bakel H, Simon V, Kirchhoff F, Jacob T, Kmiec D, Pichlmair A, Enßer A, Sparrer KMJ (2025)

Publication Type: Journal article

Publication year: 2025

Journal

iScience Elsevier

Book Volume: 28

Article Number: 112974

Journal Issue: 7

DOI: 10.1016/j.isci.2025.112974

Abstract

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.

Authors with CRIS profile

Arne Cordsmeier Institute of Clinical and Molecular Virology Armin Enßer Institute of Clinical and Molecular Virology

Involved external institutions

Universitätsklinikum Ulm DE Germany (DE) Technische Universität München (TUM) DE Germany (DE) Universität Ulm DE Germany (DE) University of Rochester Medical Center Rochester, NY US United States (USA) (US) Icahn School of Medicine at Mount Sinai US United States (USA) (US)

How to cite

APA:

Klute, S., Nchioua, R., Cordsmeier, A., Vishwakarma, J., Koepke, L., Alshammary, H.,... Sparrer, K.M.J. (2025). Mutation T9I in Envelope confers autophagy resistance to SARS-CoV-2 Omicron. iScience, 28(7). https://doi.org/10.1016/j.isci.2025.112974

MLA:

Klute, Susanne, et al. "Mutation T9I in Envelope confers autophagy resistance to SARS-CoV-2 Omicron." iScience 28.7 (2025).

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