Aminopeptidase N is a receptor for hedgehog merbecoviruses
11 affiliations
- 1Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
- 2Paul G. Allen School for Global Health, Washington State University, Pullman, WA, USA
- 3Departments of Laboratory Medicine and Immunobiology, Yale University, New Haven, CT, USA
- 4Department of Epidemiology, Gillings School of Global Public Heath, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- 5Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità, Rome, Italy
- 6Virology Department, Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna, Brescia, Italy
- 7Department of Biochemistry, University of Utah, Salt Lake City, UT, USA
- 8Cary Institute of Ecosystem Studies, Millbrook, NY, USA
- 9Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- 10Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
- 11Paul G. Allen School for Global Health, Washington State University, Pullman, WA, USA. [email protected]
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.
Related
- mTORC1-dependent control of Hedgehog signaling mediates nutrient-responsive licensing of intestinal stem cell differentiation
- Wuguchong Bioactive Peptides Promote Wound Healing via Hedgehog Pathway‑Mediated Fibroblast Modulation.
- A single-nucleus RNA atlas of the hedgehog testis reveals the cellular basis of seasonal reproduction
- Sulforaphane inhibits N-nitrosodimethylamine induced hepatocellular carcinoma stem cell properties via ZNF652/Sonic hedgehog axis.
- Glucagon-Like Peptide-1 Receptor Agonist and Gastrointestinal Adverse Effects: A Comprehensive Review Efectos adversos gastrointestinales del agonista del receptor de GLP-1: revisión narrativa
BibTeX
@article{jin2026aminopeptidase,
title = {{Aminopeptidase N is a receptor for hedgehog merbecoviruses}},
author = {Min Jin and Victoria A. Jefferson and Zhe Zhao and Nicholas Catanzaro and Luca De Sabato and Emma L. Keeler and Bridget L. Menasché and C E Hoffman and Boyd L. Yount and Anna Castelli and Ilaria Di Bartolo and Gabriele Vaccari and Tyler N. Starr and Stephanie N. Seifert and Adrian A. Castellanos and Barbara A. Han and Leonid Serebryannyy and Alicen Burns Spaulding and Daniel C. Douek and Ana Moreno and Ralph Steven Baric and Craig B. Wilen and James M. Rini and Michael C. Letko},
journal = {Nature Microbiology},
year = {2026},
month = sep,
doi = {10.1038/s41564-026-02447-8},
url = {https://doi.org/10.1038/s41564-026-02447-8},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Aminopeptidase N is a receptor for hedgehog merbecoviruses
AU - Min Jin
AU - Victoria A. Jefferson
AU - Zhe Zhao
AU - Nicholas Catanzaro
AU - Luca De Sabato
AU - Emma L. Keeler
AU - Bridget L. Menasché
AU - C E Hoffman
AU - Boyd L. Yount
AU - Anna Castelli
AU - Ilaria Di Bartolo
AU - Gabriele Vaccari
AU - Tyler N. Starr
AU - Stephanie N. Seifert
AU - Adrian A. Castellanos
AU - Barbara A. Han
AU - Leonid Serebryannyy
AU - Alicen Burns Spaulding
AU - Daniel C. Douek
AU - Ana Moreno
AU - Ralph Steven Baric
AU - Craig B. Wilen
AU - James M. Rini
AU - Michael C. Letko
PY - 2026
DA - 2026/09/16
JO - Nature Microbiology
DO - 10.1038/s41564-026-02447-8
UR - https://doi.org/10.1038/s41564-026-02447-8
AB - 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.
SN - 2058-5276
ER -