Adenoviral E3/49K: CD45-targeted immune evasion and therapeutic potential.

Human adenoviruses (HAdVs) cause a broad spectrum of diseases, ranging from mild respiratory and gastrointestinal infections to severe, sometimes even fatal illness in immunocompromised individuals. Species D adenoviruses represent the largest group, possibly driven by strong evolutionary pressure, particularly within the highly variable early transcription unit 3 (E3), which encodes immunomodulatory proteins. Among these, E3/49K is unique to species D and utilizes a particularly intriguing immunomodulatory strategy. It is a heavily glycosylated transmembrane protein that undergoes proteolytic shedding to release the soluble ectodomain (sec49K), the only known secreted HAdV protein. Both the membrane-anchored and soluble forms target the leukocyte-specific receptor-like protein tyrosine phosphatase CD45, a key regulator of immune cell activation. E3/49K binds CD45 with high affinity via two domains, inducing dimerization and inhibiting its phosphatase activity, thereby suppressing activation of T, B, and NK cells. The species specificity and potent immunomodulatory function of E3/49K underscore its role in adenoviral adaptation and highlight its potential for therapeutic immunosuppression and cancer therapy.