The E3 ubiquitin ligase Mind bomb 1 enhances nuclear import of viral DNA by inactivating a virion linchpin protein that suppresses exposure of virion pathogen-associated molecular patterns

In eukaryotic cells, genomes from incoming DNA viruses mount two opposing reactions, viral gene expression and innate immune response, depending on genome exposure (uncoating) to either RNA-polymerases or DNA sensors. Here we show that adenovirus particles contain a tunable linchpin protein with a dual function: response to host cues for scheduled DNA release into the nucleus, and innate immunity suppression by preventing unscheduled DNA release. Scheduled DNA release required the proteasome and ubiquitination of the viral core protein V. Cells lacking the E3 ligase Mind bomb 1 (Mib1) were resistant to wild-type adenovirus infection. Viruses lacking protein V or bearing non-ubiquitinable protein V, however, readily infected Mib1 knockout cells, yet were less infectious than wild-type virus. Their genomes were poorly imported into the nucleus and remained uncoated in the cytosol, thereby enhancing chemokine and interferon production through the DNA sensor cGAS. Our data uncover how the ubiquitin-proteasome system controls the function of a virion linchpin protein suppressing pathogen-associated molecular patterns and triggers viral DNA uncoating at the nuclear pore complex for nuclear import and infection.