PXD075505-1

PXD075505 is an original dataset announced via ProteomeXchange.

Title	Unveiling Alternate Pathways for SARS-CoV-2 Infection via Extracellular Vesicle-Mediated Transfer of ACE2 and TMPRSS2
Description	The COVID-19 pandemic, caused by SARS-CoV-2, has underscored the urgency of understanding viral entry mechanisms to develop effective therapeutic strategies. SARS-CoV-2 primarily exploits angiotensin-converting enzyme 2 (ACE2) as its entry receptor and relies on the serine protease TMPRSS2 to prime its spike protein, enabling membrane fusion and infection. Traditionally, TMPRSS2 has been described as a cell surface protein, but our study reveals that in human lung epithelial cells, TMPRSS2 is largely absent from the plasma membrane and instead resides intracellularly. We show that TMPRSS2 is secreted together with ACE2 in extracellular vesicles (EVs) from lung epithelial cells, which are subsequently taken up by non-epithelial cells, specifically alveolar macrophages, endothelial cells, and pericytes, that do not express TMPRSS2 or ACE2 mRNA under homeostatic conditions. This EV uptake deposits ACE2 and TMPRSS2 protein onto recipient cells, equipping them for SARS-CoV-2 entry. By transferring these viral entry proteins, EVs expand the spectrum of susceptible cell types in the lung, offering a new explanation for how the virus can infect diverse cell populations and cause widespread tissue damage. Identifying EVs as vehicles for delivering functional ACE2 and TMPRSS2 across cell types reveals previously unrecognized pathway of viral entry with important implications for COVID-19 pathogenesis. These findings open new avenues for therapeutic intervention aimed at disrupting EV-mediated protein transfer, potentially limiting viral dissemination and severity, and may also represent a generalizable mechanism exploited by other viral pathogens, highlighting the potential relevance of EV-mediated protein transfer beyond SARS-CoV-2.
HostingRepository	PRIDE
AnnounceDate	2026-03-25
AnnouncementXML	Submission_2026-03-25_07:50:07.839.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jeffrey Johnson
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2026-03-11 10:06:03	ID requested
⏵ 1	2026-03-25 07:50:08	announced

Dataset with its publication pending

submitter keyword: SARS-CoV-2, TMPRSS2, ACE2

Jeffrey Johnson
contact affiliation	Icahn School of Medicine at Mount Sinai
contact email	jeffrey.johnson@mssm.edu
lab head
Jeffrey Johnson
contact affiliation	Icahn School of Medicine at Mount Sinai
contact email	jeffrey.johnson@mssm.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/03/PXD075505

PRIDE project URI

• PRIDE
  1. PXD075505
     1. Label: PRIDE project
     2. Name: Unveiling Alternate Pathways for SARS-CoV-2 Infection via Extracellular Vesicle-Mediated Transfer of ACE2 and TMPRSS2