title: The cytomegaloviral protein pUL138 acts as potentiator of tumor necrosis factor (TNF) receptor 1 surface density to enhance ULb'-encoded modulation of TNF-α signaling.
abstract: Human cytomegalovirus is a ubiquitous herpesvirus that establishes lifelong latent infection. Changes in immune homeostasis induce the reactivation of lytic infection, which is mostly inapparent in healthy individuals but often causes overt disease in immunocompromised hosts. Based on discrepant tumor necrosis factor receptor 1 surface disposition between human cytomegalovirus AD169 variants differing in the ULb' region, we identified the latency-associated gene product pUL138, which also is expressed during productive infection, as a selective potentiator of tumor necrosis factor receptor 1, one of the key receptors of innate immunity. Ectopically expressed pUL138 coprecipitated with tumor necrosis factor receptor 1, extended the protein half-life, and enhanced its signaling responses, thus leading to tumor necrosis factor receptor 1 hyperresponsiveness. Conversely, the targeted deletion of UL138 from the human cytomegaloviral genome strongly reduced tumor necrosis factor receptor 1 surface densities of infected cells. Remarkably, the comparison of UL138 deficiency to ULb' deficiency revealed the presence of further positive modulators of tumor necrosis factor alpha signal transduction encoded within the human cytomegalovirus ULb' region, identifying this region as a hub for multilayered tumor necrosis factor alpha signaling regulation.
authors: Heinrich-Heine-Universität, Institut für Virologie, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
authors: Vu Thuy Khanh
authors: VT
authors: Le
authors: Mirko
authors: M
authors: Trilling
authors: Hartmut
authors: H
authors: Hengel
mesh_terms: D002460:Cell Line; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D017353:Gene Deletion; D054884:Host-Pathogen Interactions; D006801:Humans; D047468:Immunoprecipitation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*; D014764:Viral Proteins / Q000276:immunology / Q000378:metabolism*
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins