Regulation of Adenovirus Membrane Penetration by the Cytoplasmic Tail of Integrin β5

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Abstract
Adenovirus (Ad) cell entry involves sequential interactions with host cell receptors that mediate attachment (CAR), internalization (αvβ3 and αvβ5), and penetration (αvβ5) of the endosomal membrane. These events allow the virus to deliver its genome to the nucleus. While integrins αvβ3 and αvβ5 both promote Ad internalization into cells, integrin αvβ5 selectively facilitates Ad-mediated membrane permeabilization and endosome rupture. In the experiments reported herein, we demonstrate that the intracellular domain of the integrin β5 subunit specifically regulates Ad-mediated membrane permeabilization and gene delivery. CS-1 melanoma cells expressing a truncated integrin β5 or a chimeric (β5-β3) cytoplasmic tail (CT) supported normal levels of Ad endocytosis but had reduced Ad-mediated gene delivery and membrane permeabilization relative to cells expressing a wild-type integrin β5. Thin-section electron microscopy revealed that virion particles were capable of being endocytosed into cells expressing a truncated β5CT, but they failed to escape cytoplasmic vesicles and translocate to the nucleus. Site-specific mutagenesis studies suggest that a C-terminal TVD motif in the β5CT plays a major role in Ad membrane penetration.