Grk2 Mediates Beta-Arrestin Interactions With 5-Ht2 Receptors For Jc Polyomavirus Endocytosis
JOURNAL OF VIROLOGY(2021)
摘要
JC polyomavirus (JCPyV) infects the majority of the population, establishing a lifelong, asymptomatic infection in the kidney of healthy individuals. People who become severely immunocompromised may experience JCPyV reactivation, which can cause progressive multifocal leukoencephalopathy (PML), a neurodegenerative disease. Due to a lack of therapeutic options, PML results in fatality or significant debilitation among affected individuals. Cellular internalization of JCPyV is mediated by serotonin 5-hydroxytryptamine subfamily 2 receptors (5-HT(2)Rs) via clathrin-mediated endocytosis. The JCPyV entry process requires the clathrin-scaffolding proteins beta-arrestin, adaptor protein 2 (AP2), and dynamin. Furthermore, a beta-arrestin-interacting domain, the Ala-Ser-Lys (ASK) motif, within the C terminus of 5-HT2AR is important for JCPyV internalization and infection. Interestingly, 5-HT2R subtypes A, B, and C equally support JCPyV entry and infection, and all subtypes contain an ASK motif, suggesting a conserved mechanism for viral entry. However, the role of the 5-HT2R ASK motifs and the activation of beta-arrestin-associated proteins during internalization have not been fully elucidated. Through mutagenesis, the ASK motifs within 5-HT2BR and 5-HT2CR were identified as being critical for JCPyV internalization and infectivity. Furthermore, by using biochemical pulldown techniques, mutagenesis of the ASK motifs in 5-HT2BR and 5-HT2CR resulted in reduced beta-arrestin binding. When small-molecule chemical inhibitors and RNA interference were used, G protein receptor kinase 2 (GRK2) was determined to be required for JCPyV internalization and infection by mediating interactions between beta-arrestin and the ASK motif of 5-HT(2)Rs. These findings demonstrate that GRK2 and beta-arrestin interactions with 5-HT(2)Rs are critical for JCPyV entry by clathrin-mediated endocytosis and the resultant infection.IMPORTANCE As intracellular parasites, viruses require a host cell to replicate and cause disease. Therefore, virus-host interactions contribute to viral pathogenesis. JC polyomavirus (JCPyV) infects most of the population, establishing a lifelong asymptomatic infection within the kidney. Under conditions of severe immunosuppression, JCPyV may spread to the central nervous system, causing the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). Individuals living with HIV or undergoing immunomodulatory therapies are at risk for developing PML. The mechanisms of how JCPyV uses specific receptors on the surface of host cells to initiate internalization and infection are poorly understood processes. We have further identified cellular proteins involved in JCPyV internalization and infection and elucidated their specific interactions that are responsible for the activation of receptors. Collectively, these findings illuminate how viruses usurp cellular receptors during infection, contributing to current development efforts for therapeutic options for the treatment or prevention of PML.
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关键词
ASK motif, G protein-coupled receptor, GRK, JC polyomavirus, polyomavirus, SV40, beta arrestin, endocytosis, internalization, serotonin receptor
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