Mutation T9I in Envelope confers autophagy resistance to SARS-CoV-2 Omicron. Klute et al.
Description
Omicron has emerged as the most successful variant of SARS-CoV-2. Besides mutations in the Spike protein that promote humoral immune escape, the Omicron-specific Envelope (E) T9I mutation has been associated with increased transmission fitness. However, the underlying mechanism remained unclear. Our data show that the Omicron variants BA.1, BA.5, and XBB.1.5 are significantly more resistant to autophagy than the Delta variant or an early 2020 SARS-CoV-2 isolate. Screening of SARS-CoV-2 proteins with VOC-specific single point mutations revealed that the Omicron-specific mutation T9I in the E protein significantly enhances its ability to antagonize. Rare Omicron patient isolates encoding the ancestral E T9 remain sensitive to autophagy. Conversely, the mutation of E T9I renders recombinant 2020 SARS-CoV-2 resistant to autophagy. Our data indicate that the E T9I mutation protects SARS-CoV-2 virions against lysosomal degradation. Mechanistic analyses show the T9I mutation increases the localization of E at autophagic vesicles and interactions 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.