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

Abstract

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.

Harnessing Multi‐Modal Exciton Migration in Hybrid Halide Perovskite for Photocatalytic Amplification of Nitric Oxide and Hydroxyl Radicals toward Bacterial Killing and Biofilm Disruption

“…The mechanism of interfacial interaction between PeV heterostructure and bacterial surface was gleaned in further detail by AFM-based topographic imaging and nanoindentation studies. [57,58] AFM topography images were recorded with the dried bacterial cell (dried E. coli bacterial film immobilized on a silicon wafer) under the tapping mode (Figure 6). The height profile and amplitude mapping obtained from AFM images, reveal the characteristics of rod-shaped bacterial cells with the dimensions (height ≈219 nm and length ≈2.5 μm), typically matching with the E. coli as reported previously.…”

HSV Replication: Triggering and Repressing STING Functionality

“…During viral replication, the nucleus architecture is reorganized to accommodate newly synthesized viral DNA and viral protein components required for the viral capsid [ 78 , 79 ]. This process results in massive mechanical stress to the nucleus causing disruption of the nuclear lamina and displacement of the host chromatin [ 78 , 79 , 80 , 81 , 82 ]. The loss of nuclear envelope integrity initiates the formation micronuclei, small DNA-containing envelope-like structures indicative of chromosome instability [ 83 ].…”

“…Nuclear DNA may also be released into the cytoplasm due to defects in DNA repair processing or nuclear envelope rupture, due to various stressors, which can cause activation of the innate immune response [ 56 , 85 , 86 , 87 , 88 ] HSV infection can lead to an accumulation of single and double stranded DNA breaks within the host DNA due to downregulations in DNA repair proteins such as Ku80 leading to neurodegenerative disorders [ 89 ]. However, when HSV-1 DNA is injected into the nucleus, there is elevated occurrences of chromatin stiffness and softening of the nuclear lamina to reduce nuclear DNA damage due to deformation [ 81 , 82 ]. These data support the view that HSV infection can result in nuclear DNA damage and that the nucleus lamina softens, and chromatin stiffens to minimize DNA damage.…”