Dual signaling via interferon and DNA damage response elicits entrapment by giant PML nuclear bodies

PML nuclear bodies (PML-NBs) are dynamic interchromosomal macromolecular complexes implicated in epigenetic regulation as well as antiviral defense. During herpesvirus infection, PML-NBs induce epigenetic silencing of viral genomes, however, this defense is antagonized by viral regulatory proteins s...

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Bibliographic Details
Published in:eLife 2022-03, Vol.11
Main Authors: Scherer, Myriam, Read, Clarissa, Neusser, Gregor, Kranz, Christine, Kuderna, Anna K, Müller, Regina, Full, Florian, Wörz, Sonja, Reichel, Anna, Schilling, Eva-Maria, Walther, Paul, Stamminger, Thomas
Format: Article
Language:English
Subjects:
Antiviral Agents
cytomegalovirus
DNA Damage
Epigenesis, Genetic
herpesvirus
Humans
Interferons - metabolism
intrinsic immunity
Microbiology and Infectious Disease
Nuclear Bodies
Nuclear Proteins - metabolism
PML protein
Promyelocytic Leukemia Protein - genetics
Transcription Factors - metabolism
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Summary:PML nuclear bodies (PML-NBs) are dynamic interchromosomal macromolecular complexes implicated in epigenetic regulation as well as antiviral defense. During herpesvirus infection, PML-NBs induce epigenetic silencing of viral genomes, however, this defense is antagonized by viral regulatory proteins such as IE1 of human cytomegalovirus (HCMV). Here, we show that PML-NBs undergo a drastic rearrangement into highly enlarged PML cages upon infection with IE1-deficient HCMV. Importantly, our results demonstrate that dual signaling by interferon and DNA damage response is required to elicit giant PML-NBs. DNA labeling revealed that invading HCMV genomes are entrapped inside PML-NBs and remain stably associated with PML cages in a transcriptionally repressed state. Intriguingly, by correlative light and transmission electron microscopy (EM), we observed that PML cages also entrap newly assembled viral capsids demonstrating a second defense layer in cells with incomplete first-line response. Further characterization by 3D EM showed that hundreds of viral capsids are tightly packed into several layers of fibrous PML. Overall, our data indicate that giant PML-NBs arise via combined interferon and DNA damage signaling which triggers entrapment of both nucleic acids and proteinaceous components. This represents a multilayered defense strategy to act in a cytoprotective manner and to combat viral infections.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.73006