Abstract
Human herpesvirus 8 (HHV-8) is an oncogenic virus that enters cells by fusion of the viral and endosomal cellular membranes in a process mediated by viral surface glycoproteins. One of the cellular receptors hijacked by HHV-8 to gain access to cells is the EphA2 tyrosine kinase receptor, and the mechanistic basis of EphA2-mediated viral entry remains unclear. Using X-ray structure analysis, targeted mutagenesis, and binding studies, we here show that the HHV-8 envelope glycoprotein complex H and L (gH/gL) binds with subnanomolar affinity to EphA2 via molecular mimicry of the receptor's cellular ligands, ephrins (Eph family receptor interacting proteins), revealing a pivotal role for the conserved gH residue E52 and the amino-terminal peptide of gL. Using FSI-FRET and cell contraction assays, we further demonstrate that the gH/gL complex also functionally mimics ephrin ligand by inducing EphA2 receptor association via its dimerization interface, thus triggering receptor signaling for cytoskeleton remodeling. These results now provide novel insight into the entry mechanism of HHV-8, opening avenues for the search of therapeutic agents that could interfere with HHV-8-related diseases.
Highlights
Human herpesvirus 8 (HHV-8), known as Kaposi sarcoma (KS)-associated virus, is a member of Rhadinovirus genus that belongs to the Gammaherpesvirinae subfamily of Herpesviridae [1]
To maximize the tertiary complex formation, the glycoproteins H and L (gH/gL) was mixed with an excess of ligand-binding domain (LBD), which was removed by size exclusion chromatography (SEC)
Contrary to the many interactions provided by gL we show, in addition, that the only gH residue involved in contacts with EphA2 LBD—the E52gH—is critical for the high-affinity interactions between HHV-8 gH/gL to EphA2, with the Kd in subnanomolar range (Fig 2C)
Summary
Human herpesvirus 8 (HHV-8), known as Kaposi sarcoma (KS)-associated virus, is a member of Rhadinovirus genus that belongs to the Gammaherpesvirinae subfamily of Herpesviridae [1]. HHV-8 is an oncogenic virus and etiological agent of KS, malignancy of endothelial cells named after the Hungarian dermatologist who first described the disease in 1872 [2]. Because KS has different clinical manifestations, 2 main forms are distinguished—the classic KS that is a relatively indolent and rare tumor, appearing as skin lesions mostly in elderly men, and the epidemic or HIV-associated KS, an aggressive form that spreads extensively through skin, lymph nodes, intestines, and lungs. The KS affects up to 30% of untreated HIV–positive. Interactions between HHV-8 and cellular receptor EphA2. All other relevant data are within the paper and its Supporting Information file
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