The E3 CR1-gamma gene in human adenoviruses associated with epidemic keratoconjunctivitis

Abstract

Human adenovirus species D type 37 (HAdV-D37) is an important etiologic agent of epidemic keratoconjunctivitis. Annotation of the whole genome revealed an open reading frame (ORF) in the E3 transcription unit predicted to encode a 31.6 kDa protein. This ORF, also known as CR1-γ, is predicted to be an integral membrane protein containing N-terminal signal sequence, luminal, transmembrane, and cytoplasmic domains. HAdV-D19 (C), another viral pathogen causing epidemic keratoconjunctivitis, contains an ORF 100% identical to its HAdV-D37 homologue but only 66% identical to other HAdV-D homologues. Kinetics of RNA expression and confirmation of splicing to the adenovirus tripartite leader sequence suggest a role for the protein product of CR1-γin the late stages of the viral replication cycle. Confocal microscopy is consistent with expression in the cytoplasm. Sequence analysis reveals a hypervariable luminal domain and a conserved cytoplasmic domain. The luminal domain is predicted to contain multiple N-glycosylation sites. The cytoplasmic domain contains a putative protein kinase C phosphorylation site and potential YXXϕ and dileucine (LL) motifs suggesting a potential role in modification of host proteins.

Sorting Motifs in the Cytoplasmic Tail of the Immunomodulatory E3/49K Protein of Species D Adenoviruses Modulate Cell Surface Expression and Ectodomain Shedding

“…An additional role of the C-terminal portion would be consistent with the relatively long halflife and the high conservation of its sequence. The last 50 amino acids exhibit 84 -100% amino acid identity for different Ad types of species D, whereas that of the secreted N-terminal domain (ϳ383 amino acids) is considerably lower, ranging from ϳ36 to 55% (34,76). This N-terminal sequence diversity is consistent with the proposed recombination hot spot within E3/49K/CR1␤, which seems to drive rapid evolution and diversification of sec49K (22).…”

Molecular phylogeny of a novel human adenovirus type 8 strain causing a prolonged, multi-state keratoconjunctivitis epidemic in Germany

“…These may either impede the immune response (CR1α gene)19 or may be associated with an EKC phenotype (CR1γ gene)20. However, the significance of these mutations for virulence and disease severity of the epidemic HAdV-D8 strain cannot yet be estimated, mostly for the reason that adequate data for other HAdV-D8 strains were not yet available.…”

Analysis of Human Adenovirus Type 19 Associated with Epidemic Keratoconjunctivitis and its Reclassification as Adenovirus Type 64

“…We studied previously the CR-1 gamma open reading frame within the E3 transcription unit, which is identical between HAdV-D64 and HAdV-D37. 60 However, it is more likely that the fiber gene, and in particular the coding region for the fiber knob, represents the critical determinant for corneal tropism. Other gene products as yet uncharacterized also could influence the outcome of infection.…”