ER-export and ARFRP1/AP-1-dependent delivery of SARS-CoV-2 Envelope to lysosomes controls late stages of viral replication

Sci Adv. 2024 Apr 5;10(14):eadl5012. doi: 10.1126/sciadv.adl5012. Epub 2024 Apr 3.

Abstract

The β-coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the global COVID-19 pandemic. Coronaviral Envelope (E) proteins are pentameric viroporins that play essential roles in assembly, release, and pathogenesis. We developed a nondisruptive tagging strategy for SARS-CoV-2 E and find that, at steady state, it localizes to the Golgi and to lysosomes. We identify sequences in E, conserved across Coronaviridae, responsible for endoplasmic reticulum-to-Golgi export, and relate this activity to interaction with COP-II via SEC24. Using proximity biotinylation, we identify an ADP ribosylation factor 1/adaptor protein-1 (ARFRP1/AP-1)-dependent pathway allowing Golgi-to-lysosome trafficking of E. We identify sequences in E that bind AP-1, are conserved across β-coronaviruses, and allow E to be trafficked from Golgi to lysosomes. We show that E acts to deacidify lysosomes and, by developing a trans-complementation assay for SARS-CoV-2 structural proteins, that lysosomal delivery of E and its viroporin activity is necessary for efficient viral replication and release.

MeSH terms

  • ADP-Ribosylation Factors / metabolism
  • COVID-19*
  • Humans
  • Lysosomes / metabolism
  • Pandemics
  • SARS-CoV-2* / metabolism
  • Transcription Factor AP-1 / metabolism
  • Viral Envelope Proteins / metabolism
  • Virus Replication

Substances

  • Viral Envelope Proteins
  • Transcription Factor AP-1
  • ARFRP1 protein, human
  • ADP-Ribosylation Factors