The UL144 gene product of human cytomegalovirus activates NFkappaB via a TRAF6-dependent mechanism.
Molecular mimicry of cytokines and cytokine receptors is a strategy used by poxviruses and herpesviruses to modulate host immunity. The human cytomegalovirus (HCMV) UL144 gene, situated in the UL/b' region of the viral genome, has amino-acid sequence similarity to members of the tumour necrosis factor receptor superfamily. We report that UL144 is a potent activator of NFkappaB-induced transcription in a TRAF6-dependent manner. This NFkappaB activation enhances expression of the chemokine CCL22 through the NFkappaB responsive elements found in its promoter. In contrast to the clinical HCMV isolates, extensively passaged laboratory strains lack the UL/b' region and hence do not encode UL144. Consistent with this, infection with viruses that carry UL/b' causes NFkappaB activation and CCL22 expression, a phenotype that is not observed after infections with strains lacking the UL/b' region. Moreover, knockdown of UL144, TRAF6 or NFkappaB by specific siRNA in infections with UL144-encoding HCMV prevents the activation of CCL22 expression normally observed after infection with UL/b' positive HCMV. Upregulation of CCL22, which attracts Th2 and regulatory T cells, may help HCMV evade immune surveillance.
Poole
Emma
E
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
King
Christine A
CA
Sinclair
John H
JH
Alcami
Antonio
A
D001483:Base Sequence; D002460:Cell Line; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004279:DNA, Viral / Q000235:genetics; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018716:Molecular Mimicry; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D048029:TNF Receptor-Associated Factor 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
C515482:CCL22 protein, human; D054422:Chemokine CCL22; D019742:Chemokines, CC; D004279:DNA, Viral; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D048029:TNF Receptor-Associated Factor 6; C119624:UL144 ORF protein, Human herpesvirus 5; D014764:Viral Proteins