Abstract
Antiviral defense and virus exclusion from the cell nucleus restrict foreign nucleic acid influx and infection. How the genomes of DNA viruses evade cytosolic pattern recognition and cross the nuclear envelope is incompletely understood. Here, we show that the virion protein V of adenovirus functions as a linchpin between the genome and the capsid, thereby securing particle integrity. Absence of protein V destabilizes cytoplasmic particles and promotes premature genome release, raising cytokine levels through the DNA sensor cGAS. Non-ubiquitinable V yields stable virions, genome misdelivery to the cytoplasm, and increased cytokine levels. In contrast, normal protein V is ubiquitinated at the nuclear pore complex, dissociates from the virion depending on the E3 ubiquitin ligase Mib1 and the proteasome, and allows genome delivery into the nucleus for infection. Our data uncover previously unknown cellular and viral mechanisms of viral DNA nuclear import in pathogenesis, vaccination, gene therapy, and synthetic biology.
Highlights
Viruses coevolve with their hosts in entry, uncoating, replication, assembly, and innate and adaptive immunity [1, 2]
The results show that the viral DNA (vDNA) core–associated protein V serves as a linchpin securing the stability of cytoplasmic AdV and becomes a Mind bomb 1 (Mib1)- dependent ubiquitin-responsive target at the nuclear pore complex (NPC) facilitating the nuclear import of vDNA upon virion rupture
Mib1-KO cells are resistant to AdV-C5 infection [35] but are susceptible to AdV lacking protein V or bearing non-ubiquitinable protein V, the latter are less infectious than wild-type virus
Summary
Viruses coevolve with their hosts in entry, uncoating, replication, assembly, and innate and adaptive immunity [1, 2] Their DNA or RNA genomes give rise to two opposing reactions, viral gene expression driving infection and innate immune response restricting infection through activation of DNA and RNA sensors. Viral gene products counteract the innate immune response against the incoming virus, for example, the E1A and E1B-55K proteins of AdV blunt the interferon (IFN) response [4,5,6,7] This is important because pathogen-associated molecular patterns (PAMPs) activate the innate immune system as early as pathogen entry and boost cell defense and adaptive immunity [8].
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