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Published on: March 24, 2017
Aminopeptidase N is a receptor for hedgehog merbecoviruses
Min Jin1, Victoria A Jefferson2, Zhe Zhao3
1Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
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.
Insights
Hedgehog merbecoviruses use Aminopeptidase N (APN) to enter host cells. This discovery clarifies viral entry mechanisms and informs zoonotic risk assessments for these MERS-CoV relatives.
Area of Science:
- Virology
- Structural Biology
- Zoonosis Research
Background:
- Merbecoviruses, related to MERS-CoV, are found in hedgehogs globally.
- Concerns exist regarding zoonotic transmission potential to humans and animals.
- The host cell entry mechanism for hedgehog merbecoviruses was previously unknown.
Purpose of the Study:
- To identify the host cell entry receptor for hedgehog merbecoviruses.
- To understand the molecular basis of species barriers for merbecovirus entry.
- To inform risk assessments for potential viral emergence and zoonotic transmission.
Main Methods:
- Tested European hedgehog (Erinaceus europaeus) coronavirus receptor orthologues.
- Utilized single-cycle pseudotype and replication-competent virus assays.
- Performed protein binding assays and cryo-electron microscopy (cryo-EM).
Main Results:
- Identified Aminopeptidase N (APN) as the entry receptor for hedgehog merbecoviruses.
- Confirmed APN as the receptor using multiple experimental approaches.
- Cryo-EM revealed a unique viral glycoprotein-APN interaction interface, distinct from other betacoronaviruses.
Conclusions:
- Aminopeptidase N is a key receptor for hedgehog merbecovirus entry.
- The unique binding interface explains species-specific entry barriers.
- Findings expand knowledge of betacoronavirus receptors and zoonotic potential.
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