Aminopeptidase N is a receptor for hedgehog merbecoviruses

作者：Min Jin, Victoria A. Jefferson, Zhe Zhao, Nicholas Catanzaro, Luca De Sabato, Emma L. Keeler, Bridget L. Menasché, C E Hoffman, Anna Castelli, Ilaria Di Bartolo, G. Vaccari, Tyler N. Starr, Stephanie N. Seifert, A. Castellanos, Barbara A. Han, Leonid Serebryannyy, Alicen B. Spaulding, Daniel C. Douek, Ana Moreno, Ralph S. Baric, Craig B. Wilen, James M. Rini, Michael Letko · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.09.03.674079 · 被引用次数：9 · 研究领域：Animal Virus Infections Studies、SARS-CoV-2 and COVID-19 Research、Virus-based gene therapy research

ABSTRACT Merbecoviruses, closely related to the highly pathogenetic Middle East Respiratory Syndrome Coronavirus (MERS-CoV), circulate in hedgehogs throughout Europe and Asia, raising concerns about zoonotic transmission to humans and domestic animals. Unfortunately, how these viruses enter host cells remains unknown, hindering experimental studies. Here, we tested known coronavirus receptor orthologues from European hedgehogs ( Erinaceus europaeus ) and identified Aminopeptidase N (APN) as an entry receptor for hedgehog merbecoviruses. We confirm this result with single-cycle pseudotype and replication-competent virus experiments as well as protein binding assays. A screen of 30 mammalian APN orthologues reveals restricted cross-species receptor use. Cryo-electron microscopy analysis of the viral glycoprotein–receptor complex shows a unique interface distinct from known coronavirus spike:APN interactions, providing a molecular basis for species barriers. These findings expand the known range of receptor use not only within merbecoviruses but also betacoronaviruses, improving our understanding of betacoronavirus receptors, and informing risk assessments for viral emergence.