Abstract
Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16) are the main causative agents of hand, foot and mouth disease (HFMD) worldwide. Studies showed that EV-A71 and CV-A16 antagonize the interferon (IFN) signaling pathway; however, how IFN controls this viral infection is largely unknown. Here, we identified an IFN-stimulated gene, Transmembrane Protein 106A (TMEM106A), encoding a protein that blocks EV-A71 and CV-A16 infection. Combined approaches measuring viral infection, gene expression, and protein interactions uncovered that TMEM106A is required for optimal IFN-mediated viral inhibition and interferes with EV-A71 binding to host cells on the receptor scavenger receptor class B member 2 (SCARB2). Our findings reveal a new mechanism contributing to the IFN-mediated defense against EV-A71 and CV-A16 infection and provide a potential strategy for HFMD treatment by using the antiviral role of TMEM106A against enterovirus.
Highlights
Hand, foot and mouth disease (HFMD) is an early-onset disease mostly affecting children under 5 years of age
We showed that TMEM106A is an interferon-stimulated gene (ISG) upregulated upon type I interferon treatment and is required for optimal IFNmediated antiviral activity against Enterovirus A71 (EV-A71) infection (Figure 1)
TMEM106A blocks scavenger receptor class B member 2 (SCARB2)-mediated EV-A71 and Coxsackievirus A16 (CV-A16) infection but does not affect infections mediated by other receptors (Figure 2)
Summary
Foot and mouth disease (HFMD) is an early-onset disease mostly affecting children under 5 years of age. The binding and entry to host cells are mediated by viral capsid structure, an icosahedral viral particle composed of four structural proteins VP1, VP2, VP3, and VP4 [8]. Both EV-A71 and CV-A16 viruses predominantly use host-encoded receptor scavenger receptor class B member 2 (SCARB2) or P-selectin glycoprotein ligand (PSGL-1) as receptors [9]. CV-A10 was reported to bind to host cells via Kringle containing transmembrane protein 1 (KREMEN1) receptor [5]. Functional viral particles assemble with viral genomic RNAs, and the newly formed viral particles are released after the host cell is lysed [14]
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