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Peer-reviewedCC BYEMBO Reports

Circulating cholesterol fuels SARS-CoV-2 replication via ORF3a

  • Jennifer M Hayashi1
  • Taha Y Taha1
  • Irene P Chen1
  • Rahul K Suryawanshi1
  • Danielle L Swaney1
  • Maria McCavitt-Malvido1
  • Mauricio Montano1
  • Abdullah M Syed1
  • Mir M Khalid1
  • Camille R Simoneau1
  • Pei-Yi Chen1
  • Kristoffer E Leon1
10 more authors
  • Chia-Lin Tsou1
  • Erica Stevenson1
  • Martin Gordon1
  • Natalie R Chaplin2
  • Danielle M Jorgens2
  • Zhongde Wang3
  • Andreas S Puschnik4
  • Jennifer A Doudna1
  • Nevan J Krogan1
  • Melanie Ott1
4 affiliations
  1. 1J. David Gladstone Institutes
  2. 2Electron Microscope Laboratory, University of California
  3. 3Department of Animal, Dairy, and Veterinary Sciences, Utah State University
  4. 4Biohub
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Abstract

High levels of “bad” cholesterol increase the risk of cardiovascular disease and are also linked to more severe COVID-19, though the reason has been unclear. We show that low-density lipoprotein (LDL) directly enhances SARS-CoV-2 RNA replication, especially in the Beta variant. The viral accessory protein ORF3a is both necessary and sufficient to increase cholesterol uptake in cell culture and hamster models. ORF3a stabilizes the host LDL receptor by displacing the PCSK9 chaperone, leading to greater cholesterol entry into cells. While wild-type ORF3a disrupts endosomal acidification and limits cholesterol recycling through interaction with VPS39 (part of the HOPS complex), the Beta variant does not, allowing more efficient cholesterol recovery and stronger LDL responsiveness. Overall, our findings show that SARS-CoV-2 can directly link its replication to host cholesterol levels via ORF3a. This mechanism may help guide antiviral strategies, particularly for individuals with high cholesterol.

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Cite

BibTeXRIS
BibTeX
@article{hayashi2026circulating,
  title = {{Circulating cholesterol fuels SARS-CoV-2 replication via ORF3a}},
  author = {Jennifer M Hayashi and Taha Y Taha and Irene P Chen and Rahul K Suryawanshi and Danielle L Swaney and Maria McCavitt-Malvido and Mauricio Montano and Abdullah M Syed and Mir M Khalid and Camille R Simoneau and Pei-Yi Chen and Kristoffer E Leon and Chia-Lin Tsou and Erica Stevenson and Martin Gordon and Natalie R Chaplin and Danielle M Jorgens and Zhongde Wang and Andreas S Puschnik and Jennifer A Doudna and Nevan J Krogan and Melanie Ott},
  journal = {EMBO Reports},
  year = {2026},
  month = sep,
  doi = {10.1038/s44319-026-00907-0},
  url = {https://doi.org/10.1038/s44319-026-00907-0},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Circulating cholesterol fuels SARS-CoV-2 replication via ORF3a
AU  - Jennifer M Hayashi
AU  - Taha Y Taha
AU  - Irene P Chen
AU  - Rahul K Suryawanshi
AU  - Danielle L Swaney
AU  - Maria McCavitt-Malvido
AU  - Mauricio Montano
AU  - Abdullah M Syed
AU  - Mir M Khalid
AU  - Camille R Simoneau
AU  - Pei-Yi Chen
AU  - Kristoffer E Leon
AU  - Chia-Lin Tsou
AU  - Erica Stevenson
AU  - Martin Gordon
AU  - Natalie R Chaplin
AU  - Danielle M Jorgens
AU  - Zhongde Wang
AU  - Andreas S Puschnik
AU  - Jennifer A Doudna
AU  - Nevan J Krogan
AU  - Melanie Ott
PY  - 2026
DA  - 2026/09/01
JO  - EMBO Reports
DO  - 10.1038/s44319-026-00907-0
UR  - https://doi.org/10.1038/s44319-026-00907-0
AB  - High levels of “bad” cholesterol increase the risk of cardiovascular disease and are also linked to more severe COVID-19, though the reason has been unclear. We show that low-density lipoprotein (LDL) directly enhances SARS-CoV-2 RNA replication, especially in the Beta variant. The viral accessory protein ORF3a is both necessary and sufficient to increase cholesterol uptake in cell culture and hamster models. ORF3a stabilizes the host LDL receptor by displacing the PCSK9 chaperone, leading to greater cholesterol entry into cells. While wild-type ORF3a disrupts endosomal acidification and limits cholesterol recycling through interaction with VPS39 (part of the HOPS complex), the Beta variant does not, allowing more efficient cholesterol recovery and stronger LDL responsiveness. Overall, our findings show that SARS-CoV-2 can directly link its replication to host cholesterol levels via ORF3a. This mechanism may help guide antiviral strategies, particularly for individuals with high cholesterol.
SN  - 1469-3178
ER  -