Adenovirus Entry - Stability, Uncoating and Nuclear Import

Abstract

Adenoviruses (AdV) are wide-spread in vertebrates. They infect the respiratory and gastrointestinal tracts, the eyes, heart, liver and kidney, and are lethal to immunosuppressed people. Mastadenoviruses infecting mammals comprise several hundred different types, and many specifically infect humans. Human adenoviruses are the most widely used vectors in clinical applications, including cancer treatment and COVID-19 vaccination. AdV vectors are physically and genetically stable, and generally safe in humans. The particles have an icosahedral coat and a nucleo-protein core with a DNA genome. We describe a coherent concept of AdV entry, and highlight recent advances in cytoplasmic transport, uncoating and nuclear import of the viral DNA, including microtubule motors. We highlight a ‘linchpin’ function of the virion protein V ensuring cytoplasmic particle stability, which is relaxed at the nuclear pore complex by cues from the E3-ubiquitin ligase Mind bomb 1 (MIB1) and the proteasome triggering disruption. Capsid disruption by kinesin motor proteins and microtubules then exposes the linchpin and renders protein V a target for MIB1 ubiquitination, which dissociates V from viral DNA and enhances DNA nuclear import. These advances uncover surprising mechanisms controlling capsid stability and premature uncoating, and provide insight into nuclear transport of nucleic acids.