Pressurized DNA state inside herpes capsids—A novel antiviral target

Brandariz-Núñez, Alberto; Robinson, S.; Evilevitch, Alex

doi:10.1371/journal.ppat.1008604

Cited by 26 publications

(20 citation statements)

References 91 publications

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“…Wheat germ agglutinin (WGA) was previously shown to bind Phenylalanine-Glycine (FG) in NPCs and to inhibit export [ 44 , 45 ]. WGA and capsids interact with the nuclear pores from the cytoplasmic direction and high dose WGA (0.1–0.5 mg/mL) prevents the docking of capsids at the nuclear pores [ 36 , 46 ]. At a low dose (5 µg/mL), WGA was shown to block mRNA export [ 42 , 47 , 48 ].…”

Section: Resultsmentioning

confidence: 99%

“…Upon proper docking at the nuclear pores, the viral genome is rapidly released through the portal into the nucleoplasm. Ejection of the genome from the capsid is promoted by the high internal pressure of tens of atmospheres, which forcefully overcomes the NPC permeability barrier to enter into the nucleus [ 34 , 35 , 36 , 37 ]. Whether the docking of the capsid at the NPC is a stochastic event or driven to the correct orientation by the structure of the unique portal vertex is currently unknown.…”

Section: Introductionmentioning

confidence: 99%

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The Portal Vertex of KSHV Promotes Docking of Capsids at the Nuclear Pores

Dünn-Kittenplon

Ashkenazy-Titelman

Kalt

et al. 2021

Viruses

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Kaposi’s sarcoma-associated herpesvirus (KSHV) is a cancer-related herpesvirus. Like other herpesviruses, the KSHV icosahedral capsid includes a portal vertex, composed of 12 protein subunits encoded by open reading frame (ORF) 43, which enables packaging and release of the viral genome into the nucleus through the nuclear pore complex (NPC). Capsid vertex-specific component (CVSC) tegument proteins, which directly mediate docking at the NPCs, are organized on the capsid vertices and are enriched on the portal vertex. Whether and how the portal vertex is selected for docking at the NPC is unknown. Here, we investigated the docking of incoming ORF43-null KSHV capsids at the NPCs, and describe a significantly lower fraction of capsids attached to the nuclear envelope compared to wild-type (WT) capsids. Like WT capsids, nuclear envelope-associated ORF43-null capsids co-localized with different nucleoporins (Nups) and did not detach upon salt treatment. Inhibition of nuclear export did not alter WT capsid docking. As ORF43-null capsids exhibit lower extent of association with the NPCs, we conclude that although not essential, the portal has a role in mediating the interaction of the CVSC proteins with Nups, and suggest a model whereby WT capsids can dock at the nuclear envelope through a non-portal penton vertex, resulting in an infection ‘dead end’.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Portal Vertex of KSHV Promotes Docking of Capsids at the Nuclear Pores

Dünn-Kittenplon

Ashkenazy-Titelman

Kalt

et al. 2021

Viruses

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“…The concatemeric DNA is translocated and cleaved, leaving a unit-length genome within the nucleocapsid 14 – 18 . Biochemical data show that DNA cleavage in herpesviruses is both sequence-specific (pac motif) 14 and pressure-dependent (head-full mechanism) 19 – 22 .…”

Section: Introductionmentioning

confidence: 99%

Structural basis for genome packaging, retention, and ejection in human cytomegalovirus

Pang

Dong

et al. 2021

Nat Commun

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How the human cytomegalovirus (HCMV) genome—the largest among human herpesviruses—is packaged, retained, and ejected remains unclear. We present the in situ structures of the symmetry-mismatched portal and the capsid vertex-specific components (CVSCs) of HCMV. The 5-fold symmetric 10-helix anchor—uncommon among known portals—contacts the portal-encircling DNA, which is presumed to squeeze the portal as the genome packaging proceeds. We surmise that the 10-helix anchor dampens this action to delay the portal reaching a “head-full” packaging state, thus facilitating the large genome to be packaged. The 6-fold symmetric turret, latched via a coiled coil to a helix from a major capsid protein, supports the portal to retain the packaged genome. CVSCs at the penton vertices—presumed to increase inner capsid pressure—display a low stoichiometry, which would aid genome retention. We also demonstrate that the portal and capsid undergo conformational changes to facilitate genome ejection after viral cell entry.

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“…3 D shows the histogram distribution of C-capsids/isolated nucleus with a mean value of ∼170. We previously showed using ultrathin-sectioning EM that ∼77% of C-capsids bound to an isolated nucleus eject their DNA ( 49 ). Thus, on average, ∼130 HSV-1 genomes are released into each nucleus.…”

Section: Resultsmentioning

confidence: 99%

Intranuclear HSV-1 DNA ejection induces major mechanical transformations suggesting mechanoprotection of nucleus integrity

Evilevitch

Hohlbauch

2022

Proc. Natl. Acad. Sci. U.S.A.

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Maintaining nuclear integrity is essential to cell survival when exposed to mechanical stress. Herpesviruses, like most DNA and some RNA viruses, put strain on the nuclear envelope as hundreds of viral DNA genomes replicate and viral capsids assemble. It remained unknown, however, how nuclear mechanics is affected at the initial stage of herpesvirus infection—immediately after viral genomes are ejected into the nuclear space—and how nucleus integrity is maintained despite an increased strain on the nuclear envelope. With an atomic force microscopy force volume mapping approach on cell-free reconstituted nuclei with docked herpes simplex type 1 (HSV-1) capsids, we explored the mechanical response of the nuclear lamina and the chromatin to intranuclear HSV-1 DNA ejection into an intact nucleus. We discovered that chromatin stiffness, measured as Young’s modulus, is increased by ∼14 times, while nuclear lamina underwent softening. Those transformations could be associated with a mechanism of mechanoprotection of nucleus integrity facilitating HSV-1 viral genome replication. Indeed, stiffening of chromatin, which is tethered to the lamina meshwork, helps to maintain nuclear morphology. At the same time, increased lamina elasticity, reflected by nucleus softening, acts as a “shock absorber,” dissipating the internal mechanical stress on the nuclear membrane (located on top of the lamina wall) and preventing its rupture.

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Pressurized DNA state inside herpes capsids—A novel antiviral target

Cited by 26 publications

References 91 publications

The Portal Vertex of KSHV Promotes Docking of Capsids at the Nuclear Pores

The Portal Vertex of KSHV Promotes Docking of Capsids at the Nuclear Pores

Structural basis for genome packaging, retention, and ejection in human cytomegalovirus

Intranuclear HSV-1 DNA ejection induces major mechanical transformations suggesting mechanoprotection of nucleus integrity

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