The UL144 gene product of human cytomegalovirus activates NFB via a TRAF6dependent 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/b0 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 NFjB-induced transcription in a TRAF6-dependent manner. This NFjB activation enhances expression of the chemokine CCL22 through the NFjB responsive elements found in its promoter. In contrast to the clinical HCMV isolates, extensively passaged laboratory strains lack the UL/b0 region and hence do not encode UL144. Consistent with this, infection with viruses that carry UL/b0 causes NFjB activation and CCL22 expression, a phenotype that is not observed after infections with strains lacking the UL/b0 region. Moreover, knockdown of UL144, TRAF6 or NFjB by specific siRNA in infections with UL144-encoding HCMV prevents the activation of CCL22 expression normally observed after infection with UL/b0 positive HCMV. Upregulation of CCL22, which attracts Th2 and regulatory T cells, may help HCMV evade immune surveillance. The EMBO Journal (2006) 25, 4390–4399. doi:10.1038/ sj.emboj.7601287; Published online 24 August 2006 Subject Categories: immunology; microbiology & pathogens