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

Abstract

Significance Human adenoviruses encode Early region 3 (E3) proteins that manipulate the host immune response to establish an infection or to persist longer. To date, only a few E3 functions from a single adenovirus species (C) have been characterized, all of which act directly on infected cells. Here we describe a secreted E3 protein that is uniquely expressed by species D adenoviruses. This protein targets noninfected leukocytes using a cell surface phosphatase as a receptor. We provide evidence that this interaction suppresses leukocyte activation and effector functions, implying that species D adenoviruses can affect the host distant from the site of infection.

Expression of the Human Cytomegalovirus UL11 Glycoprotein in Viral Infection and Evaluation of Its Effect on Virus-Specific CD8 T Cells

“…Notably, for the related adenovirus type 19a E3/49K protein, modulation of lymphocyte functions was observed only for the soluble protein and not for the membrane-resident version (51).…”

“…This viral coding strategy seems to be much more common (3) than was previously anticipated. The question for a potential function of the small cleavage products of the adenovirus type 19a E3/49K protein was posed recently (51). For the small UL11 proteins, this point has to await their more careful characterization, for instance, the precise definition of the initiation codons.…”

Novel bat adenoviruses with an extremely large E3 gene

“…Other E3 proteins protect host cells against apoptosis by down-regulating apoptosis receptors or blocking TNF-a-induced signalling (Horton et al, 1991;Shisler et al, 1997;Stewart et al, 1995). Results from a recent study revealed a unique immunomodulatory pathway that a species-specific E3 gene of HAdV-D manipulates to control the functions of noninfected leukocytes (Windheim et al, 2013). Due to its extremely large size, the E3l protein contains more transmembrane domains and immune-related motifs than the E3 proteins of HAdVs, which suggests that E3l may regulate immunomodulatory pathways and disease patterns that are distinct from those noted for the known E3 genes.…”

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

“…A few E3 genes are unique to a particular species and hence may allow for speciesspecific immunomodulation and differential disease outcome (3,17,18,30,31). However, with the exception of E3/49K (32), no immune evasion function for species-specific E3 proteins has been identified to date.…”

“…E3/49K exhibits a novel processing pathway for E3 proteins. Approximately 1 h after synthesis, it is cleaved by an unknown cellular protease N-terminal to the transmembrane domain, generating a small membrane-integrated 12-14-kDa C-terminal fragment and a large ectodomain (sec49K) that is secreted or shed (32,37). sec49K is the first secreted E3 protein and the first secreted adenovirus protein known to date.…”