The UL144 gene product of human cytomegalovirus activates NFκB 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 NF kappa B-induced transcription in a TRAF6-dependent manner. This NF kappa B activation enhances expression of the chemokine CCL22 through the NF kappa B 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 NF kappa B 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 NF kappa B 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.