Human cytomegalovirus G protein-coupled receptor US28 promotes latency by attenuating c-fos.

Krishna, Benjamin A; Humby, Monica S; Miller, William E; O'Connor, Christine M

Krishna, Benjamin A; Humby, Monica S; Miller, William E; O'Connor, Christine M.

Afiliación

Krishna BA; Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106.
Humby MS; Department of Microbiology & Immunology, University at Buffalo, The State University of New York, Buffalo, NY 14203.
Miller WE; Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267.
O'Connor CM; Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106; oconnoc6@ccf.org.

Proc Natl Acad Sci U S A ; 116(5): 1755-1764, 2019 01 29.

Article en En | MEDLINE | ID: mdl-30647114

RESUMEN

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that undergoes latency in cells of the hematopoietic compartment, although the mechanisms underlying establishment and maintenance of latency remain elusive. We previously reported that the HCMV-encoded G protein-coupled receptor (GPCR) homolog US28 is required for successful latent infection. We now show that US28 protein (pUS28) provided in trans complements the US28Δ lytic phenotype in myeloid cells, suggesting that sustained US28 expression is necessary for long-term latency. Furthermore, expression of pUS28 at the time of infection represses transcription from the major immediate early promoter (MIEP) within 24 h. However, this repression is only maintained in the presence of continual pUS28 expression provided in trans Our data also reveal that pUS28-mediated signaling attenuates both expression and phosphorylation of cellular fos (c-fos), an AP-1 transcription factor subunit, to repress MIEP-driven transcription. AP-1 binds to the MIEP and promotes lytic replication, and in line with this we find that US28Δ infection results in an increase in AP-1 binding to the MIEP, compared with WT latent infection. Pharmacological inhibition of c-fos represses the MIEP during US28Δ infection to levels similar to those we observe during WT latent infection. Together, our data reveal that US28 is required for both establishment and long-term maintenance of HCMV latency, which is modulated, at least in part, by repressing functional AP-1 binding to the MIEP.

Asunto(s)

Infecciones por Citomegalovirus/virología; Citomegalovirus/genética; Receptores de Quimiocina/genética; Receptores Acoplados a Proteínas G/genética; Proteínas Virales/genética; Latencia del Virus/genética; Línea Celular; Regulación Viral de la Expresión Génica/genética; Células HEK293; Humanos; Regiones Promotoras Genéticas/genética; Transducción de Señal/genética; Factor de Transcripción AP-1/genética; Replicación Viral/genética

Palabras clave

HCMV; US28; cytomegalovirus; herpesvirus; latency

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Virales / Latencia del Virus / Infecciones por Citomegalovirus / Receptores de Quimiocina / Citomegalovirus / Receptores Acoplados a Proteínas G Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos

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