Adenovirus entry: Stability, uncoating, and nuclear import

Abstract

Adenoviruses (AdVs) are widespread 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 nucleoprotein core with a DNA genome. We describe the concept of AdV cell entry and highlight recent advances in cytoplasmic transport, uncoating, and nuclear import of the viral DNA. We highlight a recently discovered “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 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 mechanisms controlling capsid stability and premature uncoating and provide insight into nuclear transport of nucleic acids.

Human Adenovirus Gene Expression and Replication Is Regulated through Dynamic Changes in Nucleoprotein Structure throughout Infection

“…Protein VI possesses membrane lytic activity [ 56 ] and mediates rupture of the endosome and release of the virus [ 75 ]. As the capsid is transported to the nucleus along the microtubule network [ 76 ], it is progressively dismantled [ 77 , 78 , 79 ]. Upon reaching the nuclear pore, protein V is released from the viral genome following ubiquitination by the E3 ligase Mind bomb 1 [ 62 , 78 ], which allows release of the protein-VII-wrapped HAdV DNA and subsequent import into the nucleus [ 62 , 77 , 78 , 79 , 80 , 81 , 82 ].…”

“…As the capsid is transported to the nucleus along the microtubule network [ 76 ], it is progressively dismantled [ 77 , 78 , 79 ]. Upon reaching the nuclear pore, protein V is released from the viral genome following ubiquitination by the E3 ligase Mind bomb 1 [ 62 , 78 ], which allows release of the protein-VII-wrapped HAdV DNA and subsequent import into the nucleus [ 62 , 77 , 78 , 79 , 80 , 81 , 82 ]. Both viral DNA replication and progeny formation occur within the nucleus, and one infectious cycle takes 24–36 h in immortalized cells, although the time for completion of the lifecycle is slightly extended in primary cells.…”

“…Within the viral capsid, condensed viral DNA is wrapped in protein VII [ 50 ] (1). After entry into the cell, the protein-VII-wrapped DNA is translocated into the nucleus [ 77 , 78 , 79 , 80 , 81 , 82 ] (2) and is subsequently remodeled, possibly involving TAF-Iβ [ 87 ], removing some protein VII from viral DNA and decondensing the genome (3). Cellular histones are deposited onto viral DNA [ 89 , 95 , 96 , 112 ], possibly by HIRA [ 95 ] and other histone chaperones (4), allowing for more efficient early gene expression.…”

Lactate dehydrogenase and the severity of adenoviral pneumonia in children: A meta-analysis

“…Adenovirus belongs to the family Adenoviridae, which is characterized by its non-enveloped and double-stranded DNA properties ( 1 ). It has been discovered that there are at least 90 genotypes of human adenovirus, which can be divided into seven species from A to G ( 2 ).…”

Sequence-Specific Features of Short Double-Strand, Blunt-End RNAs Have RIG-I- and Type 1 Interferon-Dependent or -Independent Anti-Viral Effects

“…Pioneering as well as large scale siRNA screens have been conducted with several different viruses, for example the negative-stranded segmented RNA virus influenza A virus [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ], the positive-sense RNA viruses severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 [ 14 , 15 , 16 ], and the double-stranded DNA virus adenovirus (AdV) [ 2 , 10 , 17 ]. However, there has generally been a limited overlap in the pro- or anti-viral genes identified for a given virus in the different screens [ 18 , 19 , 20 ]. Typically, viruses take advantage of cellular miRs or encode viral miRs [ 21 ].…”