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Delivery of US28 by incoming HCMV particles rapidly attenuates Akt activity to suppress HCMV lytic replication in monocytes.
Mahmud, Jamil; Geiler, Brittany W; Biswas, Juthi; Miller, Michael J; Myers, Julia E; Matthews, Stephen M; Wass, Amanda B; O'Connor, Christine M; Chan, Gary C.
Afiliación
  • Mahmud J; Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
  • Geiler BW; Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
  • Biswas J; Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
  • Miller MJ; Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
  • Myers JE; Infection Biology, Lerner Research Institute, Sheikha Fatima bint Mubarak Global Center for Pathogen and Human Health Research, Cleveland Clinic, Cleveland, OH 44195, USA.
  • Matthews SM; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.
  • Wass AB; Infection Biology, Lerner Research Institute, Sheikha Fatima bint Mubarak Global Center for Pathogen and Human Health Research, Cleveland Clinic, Cleveland, OH 44195, USA.
  • O'Connor CM; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.
  • Chan GC; Infection Biology, Lerner Research Institute, Sheikha Fatima bint Mubarak Global Center for Pathogen and Human Health Research, Cleveland Clinic, Cleveland, OH 44195, USA.
Sci Signal ; 17(851): eadn8727, 2024 08 27.
Article en En | MEDLINE | ID: mdl-39190708
ABSTRACT
Establishing a nonproductive, quiescent infection within monocytes is essential for the spread of human cytomegalovirus (HCMV). We investigated the mechanisms through which HCMV establishes a quiescent infection in monocytes. US28 is a virally encoded G protein-coupled receptor (GPCR) that is essential for silent infections within cells of the myeloid lineage. We found that preformed US28 was rapidly delivered to monocytes by HCMV viral particles, whereas the de novo synthesis of US28 was delayed for several days. A recombinant mutant virus lacking US28 (US28Δ) was unable to establish a quiescent infection, resulting in a fully productive lytic infection able to produce progeny virus. Infection with US28Δ HCMV resulted in the phosphorylation of the serine and threonine kinase Akt at Ser473 and Thr308, in contrast with the phosphorylation of Akt only at Ser473 after WT viral infection. Inhibiting the dual phosphorylation of Akt prevented the lytic replication of US28Δ, and ectopic expression of a constitutively phosphorylated Akt variant triggered lytic replication of wild-type HCMV. Mechanistically, we found that US28 was necessary and sufficient to attenuate epidermal growth factor receptor (EGFR) signaling induced during the entry of WT virus, which led to the site-specific phosphorylation of Akt at Ser473. Thus, particle-delivered US28 fine-tunes Akt activity by limiting HCMV-induced EGFR activation during viral entry, enabling quiescent infection in monocytes.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Virales / Replicación Viral / Monocitos / Citomegalovirus / Proteínas Proto-Oncogénicas c-akt / Receptores ErbB Límite: Humans Idioma: En Revista: Sci Signal Asunto de la revista: CIENCIA / FISIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Virales / Replicación Viral / Monocitos / Citomegalovirus / Proteínas Proto-Oncogénicas c-akt / Receptores ErbB Límite: Humans Idioma: En Revista: Sci Signal Asunto de la revista: CIENCIA / FISIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos