ACE2-EGFR-MAPK signaling contributes to SARS-CoV-2 infection

• Published in: Life science alliance 2023-09, Vol.6 (9), p.e202201880
• Main Authors: Engler, Melanie, Albers, Dan, Von Maltitz, Pascal, Groß, Rüdiger, Münch, Jan, Cirstea, Ion Cristian
• Format: Article
• Language: English
• Subjects: Angiotensin-Converting Enzyme 2 - metabolism; COVID-19; ErbB Receptors - metabolism; Humans; Peptidyl-Dipeptidase A - metabolism; SARS-CoV-2 - metabolism
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.202201880

SARS-CoV-2 triggered the most severe pandemic of recent times. To enter into a host cell, SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2). However, subsequent studies indicated that other cell membrane receptors may act as virus-binding partners. Among these receptors, the epidermal growth factor receptor (EGFR) was hypothesized not only as a spike protein binder, but also to be activated in response to SARS-CoV-2. In our study, we aim at dissecting EGFR activation and its major downstream signaling pathway, the mitogen-activated signaling pathway (MAPK), in SARS-CoV-2 infection. Here, we demonstrate the activation of EGFR-MAPK signaling axis by the SARS-CoV-2 spike protein and we identify a yet unknown cross talk between ACE2 and EGFR that regulated ACE2 abundance and EGFR activation and subcellular localization, respectively. By inhibiting the EGFR-MAPK activation, we observe a reduced infection with either spike-pseudotyped particles or authentic SARS-CoV-2, thus indicating that EGFR serves as a cofactor and the activation of EGFR-MAPK contributes to SARS-CoV-2 infection.