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Proline-rich regions and motifs in trafficking: from ESCRT interaction to viral exploitation.

ABSTRACT: Most membrane-enveloped viruses bud from infected cells by hijacking the host ESCRT machinery. The ESCRTs are recruited to the budding sites by viral proteins that contain short proline (Pro)-rich motifs (PRMs) known as late domains. The late domains probably evolved by co-opting host PRMs involved in the normal functions of ESCRTs in endosomal sorting and cytokinesis. The solution and crystal structures of PRMs bound to their interaction partners explain the conserved roles of Pro and other residues that predominate in these sequences. PRMs are often grouped together in much larger Pro-rich regions (PRRs) of as many as 150 residues. The PRR of the ESCRT-associated protein, ALIX, autoregulates its conformation and activity. The robustness of different viral budding and host pathways to impairments in Pro-based interactions varies considerably. The known biology of PRM recognition in the ESCRT pathway seems, in principle, compatible with antiviral development, given our increasingly nuanced understanding of the relative weakness and robustness of the host and viral processes.

SUBMITTER: Ren X

PROVIDER: S-EPMC3158961 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Proline-rich regions and motifs in trafficking: from ESCRT interaction to viral exploitation.

Ren Xuefeng X Hurley James H JH

Traffic (Copenhagen, Denmark) 20110513 10

Most membrane-enveloped viruses bud from infected cells by hijacking the host ESCRT machinery. The ESCRTs are recruited to the budding sites by viral proteins that contain short proline (Pro)-rich motifs (PRMs) known as late domains. The late domains probably evolved by co-opting host PRMs involved in the normal functions of ESCRTs in endosomal sorting and cytokinesis. The solution and crystal structures of PRMs bound to their interaction partners explain the conserved roles of Pro and other res ...[more]

PMID: 21518163

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Project description:Lytic infection of human parvovirus B19 (B19V) takes place exclusively in human erythroid progenitor cells of bone marrow and fetal liver, which disrupts erythropoiesis. During infection, B19V expresses three nonstructural proteins (NS1, 11-kDa, and 7.5-kDa) and two structural proteins (VP1 and VP2). While NS1 is essential for B19V DNA replication, 11-kDa enhances viral DNA replication significantly. In this study, we confirmed the enhancement role of 11-kDa in viral DNA replication and elucidated the underlying mechanism. We found that 11-kDa specially interacts with cellular growth factor receptor-bound protein 2 (Grb2) during virus infection and in vitro We determined a high affinity interaction between 11-kDa and Grb2 that has an equilibrium dissociation constant (KD ) value of 18.13?nM. In vitro, one proline-rich motif was sufficient for 11-kDa to sustain a strong interaction with Grb2. In consistence, in vivo during infection, one proline-rich motif was enough for 11-kDa to significantly reduce phosphorylation of extracellular signal-regulated kinase (ERK). Mutations of all three proline-rich motifs of 11-kDa abolished its capability to reduce ERK activity and, accordingly, decreased viral DNA replication. Transduction of a lentiviral vector encoding a short hairpin RNA (shRNA) targeting Grb2 decreased the expression of Grb2 as well as the level of ERK phosphorylation, which resulted in an increase of B19V replication. These results, in concert, indicate that the B19V 11-kDa protein interacts with cellular Grb2 to downregulate ERK activity, which upregulates viral DNA replication.IMPORTANCE Human parvovirus B19 (B19V) infection causes hematological disorders and is the leading cause of nonimmunological fetal hydrops during pregnancy. During infection, B19V expresses two structural proteins, VP1 and VP2, and three nonstructural proteins, NS1, 11-kDa, and 7.5-kDa. While NS1 is essential, 11-kDa plays an enhancing role in viral DNA replication. Here, we elucidated a mechanism underlying 11-kDa protein-regulated B19V DNA replication. 11-kDa is tightly associated with cellular growth factor receptor-bound protein 2 (Grb2) during infection. In vitro, 11-kDa interacts with Grb2 with high affinity through three proline-rich motifs, of which at least one is indispensable for the regulation of viral DNA replication. 11-kDa and Grb2 interaction disrupts extracellular signal-regulated kinase (ERK) signaling, which mediates upregulation of B19V replication. Thus, our study reveals a novel mechanism of how a parvoviral small nonstructural protein regulates viral DNA replication by interacting with a host protein that is predominately expressed in the cytoplasm.

Dataset Information

Proline-rich regions and motifs in trafficking: from ESCRT interaction to viral exploitation.

Publications

Proline-rich regions and motifs in trafficking: from ESCRT interaction to viral exploitation.

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