Drifting Motions of the Adenovirus Receptor CAR and Immobile Integrins Initiate Virus Uncoating and Membrane Lytic Protein Exposure

SummaryViral particle binding to plasma membrane receptors elicits virus motions, recruits signaling proteins, and triggers membrane bending and fission, finally resulting in endocytic virus uptake. Here we analyze how human adenovirus engages its receptor coxsackievirus adenovirus receptor (CAR) and coreceptor αv integrin to move on the plasma membrane. Virus binding to CAR through fiber knobs gave rise to diffusive motions and actomyosin-2-dependent drifts, while integrin-targeted viruses were spatially more confined. Diffusions, drifts, and confined motions were specifically observed with viral particles that were subsequently internalized. CAR-mediated drifts together with integrin binding supported fiber shedding from adenovirus particles, leading to exposure of the membrane-lytic internal virion protein VI and enhanced viral escape from endosomes. Our results show that adenovirus uncoating is initiated at the plasma membrane by CAR drifting motion and binding to immobile integrins.

► Diffusion, drifts, and confined motions of adenovirus (Ad2) occur prior to endocytosis
► Diffusion and drifts require CAR, drifts are mediated by dynamic actin and myosin-2
► Ad2 targeted to αv integrins in the absence of CAR has reduced drifts and infection
► Drifts and integrin contacts promote Ad2 uncoating and membrane-lytic protein exposure