Homology between the human cytomegalovirus RL11 gene family and human adenovirus E3 genes

Abstract

A significant proportion of the human cytomegalovirus (HCMV) genome comprises 12 multigene families that probably arose by gene duplication. One, the RL11 family, contains 12 members, most of which are predicted to encode membrane glycoproteins. Comparisons of sequences near the left end of the genome in several HCMV strains revealed two adjacent open reading frames that potentially encode related proteins: RL6, which is hypervariable, and RL5A, which has not been recognized previously. These genes potentially encode a domain that is the hallmark of proteins encoded by the RL11 family, and thus constitute two new members. A homologous domain is also present in a subset of human adenovirus E3 membrane glycoproteins. Evolution of genes specifying the shared domain in cytomegaloviruses and adenoviruses is characterized by extensive divergence, gene duplication and selective sequence loss. These features prompt speculation about the roles of these genes in the two virus families.Human cytomegalovirus (HCMV; human herpesvirus 5) is the most complex human herpesvirus. The 229 354 bp genome of a high passage laboratory strain (AD169) was characterized by Chee et al. (1990) and predicted to contain 189 putative protein-coding genes, some duplicated in the inverted repeats. Subsequent revisions, based largely on comparisons with chimpanzee cytomegalovirus (CCMV), the closest known relative of HCMV, indicated that the wild-type HCMV genome contains 164-167 genes (Davison et al., 2003). Chee et al. (1990) identified nine multigene families in AD169, and an additional three were recognized in low passage isolates (Davison et al., 2003). One, the RL11 family, consists of 12 genes (RL11, RL12, RL13, UL1, UL4, UL5, UL6, UL7, UL8, UL9, UL10 and UL11) oriented left to right near the left terminus of the genome and arranged contiguously but for the presence on the opposing strand of two unrelated genes (UL2 and UL3). RL11, RL12 and the 59-portion of RL13 are present twice in the AD169 genome by virtue of their location in an inverted repeat. This repeat is much smaller in low passage strains, which consequently contain single copies of these genes (Prichard et al., 2001). RL13 is also disrupted by a frameshift in AD169 (Yu et al., 2002). All members of the RL11 family (generically termed 'RL11 genes') are dispensable for virus growth in cell culture (Ripalti & Mocarski, 1991;Hobom et al., 2000;Yu et al., 2002; Atalay et al., 2002). RL11 genes are also present in CCMV, which has counterparts of all but UL1 (Davison et al., 2003). Cytomegaloviruses of mouse, rat and tupaia lack RL11 genes (Rawlinson et al., 1996;Vink et al., 2000;Bahr & Darai, 2001).The present work involved sequence analysis of the region near the left genome terminus in six HCMV strains. Four had been grown in human fibroblast cell lines, three of these (Merlin, 3157 and 6397) derived in Cardiff by three passages from urine samples from congenitally infected infants and one a widely used low passage strain (Toledo; Quinnan et al., 1984). DNA from the Cardiff st...

A unique secreted adenovirus E3 protein binds to the leukocyte common antigen CD45 and modulates leukocyte functions

“…Considering that most E3 proteins are involved in immune evasion and E3/49K is secreted, we hypothesized that unlike all other E3 gene products characterized to date that directly modulate functions of infected cells, sec49K may target surrounding cells, most likely cells associated with the immune system. This hypothesis is supported by the presence of an unusual putative Ig domain in E3/49K (24,27 (Fig. 3A).…”

“…It was recently reported that the human cytomegalovirus (HCMV) protein pUL11 of the RL11 family fused to the Fc domain of human Ig also is able to attach to CD45, causing impaired T-cell proliferation and cytokine production and overall T-cell paralysis (40). Based on sequence comparisons, a structural relationship between E3/49K and the HCMV RL11 family was suggested by Davison et al (27). By altering the boundaries of the E3/49K CR1 repeat domain (25), these authors identified a homologous domain in other E3 proteins as well as in the HCMV RL11 family.…”

The Presence of p53 Influences the Expression of Multiple Human Cytomegalovirus Genes at Early Times Postinfection

“…Ϫ/Ϫ cells in our microarray study: UL16 (an immunoevasin), US2, UL75 (envelope glycoprotein H), UL100, and RL5A (which belongs to the RL11 glycoprotein family) (14). The damaged appearance of virions shed from p53 Ϫ/Ϫ cells, observed in our unpublished electron microscopy studies, and the poor infectivity of these shed virions may be explained by the lack of glycoprotein transcripts.…”

Reconstruction of the complete human cytomegalovirus genome in a BAC reveals RL13 to be a potent inhibitor of replication

“…Despite remarkable sequence variation among HCMV strains, UL146 and UL74 are stable within individual patients, and identical UL146 sequences have been detected in geographically distant individuals (35,66). RL13 is one of 14 members of the RL11 gene family, which is believed to have arisen through gene duplication and then diverged during the evolution of the primate cytomegaloviruses (72). Several other members of this family are also hypervariable.…”