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Cellular expression of Ebola virus VP24 protein compromises the integrity of the nuclear envelope and induces a laminopathy-like cellular phenotype

ABSTRACT: Ebola virus VP24 protein is a minor matrix protein that inhibits interferon (IFN) gene expression and counteracts the IFN-mediated antiviral response by both direct interaction with STAT1 and binding to karyopherins to prevent them from transporting STAT1 to the nucleus. Proteomic studies to identify additional EBOV VP24 partners have pointed to the nuclear membrane component emerin as a potential element of the VP24 cellular interactome. Here, we have further studied this interaction and its impact on cell phenotype. We demonstrate that VP24 interacts with emerin but also with other components of the inner nuclear membrane such as lamin A/C and lamin B, and induces their displacement to the cytoplasm. We also show that VP24 diminishes the interaction between emerin and lamin A/C and compromises the integrity of the nuclear membrane, inducing nuclear morphological abnormalities, activating a DNA damage response, the activation of ERK and the induction of ISG15. Furthermore, expression of VP24 promoted cytoplasmic translocation and downmodulation of barrier to autointegration factor 1 (BANF1), a common interactor of lamin A/C and emerin, and repression of the BAF-regulated CSF1 gene. Importantly, some of the phenotypic characteristics induced by expressing VP24 were confirmed in EBOV infected cells. In summary, here we demonstrate that VP24 acts at the nuclear membrane causing morphological and functional changes in the cells that recapitulates some of the hallmarks of laminopathy diseases.

ORGANISM(S): Chlorocebus sabaeus

PROVIDER: GSE155936 | GEO | 2021/06/10

REPOSITORIES: GEO

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Project description:The cytoplasmic functions of Wiskott-Aldrich Syndrome family (WASP) proteins are well known and include roles in cytoskeleton reorganization and membrane-cytoskeletal interactions important for membrane/vesicle trafficking, morphogenesis, immune response and signal transduction. Mis-regulation of these proteins is associated with immune deficiency and metastasis. Cytoplasmic WASP proteins act as effectors of Rho family GTPases and polymerize branched actin through the Arp2/3 complex. However, recent evidence has revealed that this classically cytoplasmic protein family also functions in the nucleus. Previously, we identified Drosophila washout (wash) as a new member of the WASP family with essential cytoplasmic roles in early development. Here we show that Wash is also present in the nucleus and plays a key role in nuclear organization via its interaction with Lamin Dm0 at the nuclear envelope. Wash and Lamin Dm0 occupy similar genomic regions that overlap with transcriptionally silent chromatin including constitutive heterochromatin. Strikingly, wash mutant and knockdown nuclei exhibit the same abnormal wrinkled morphology observed in diverse laminopathies, including the Hutchinson-Gilford progeria syndrome, and consistent with disruption of the nuclear organization of several sub-nuclear structures including cajal bodies and the chromocenter in salivary glands. We also found that Wash and Lamin knockdown disrupt chromatin accessibility of repressive compartments in agreement with an observed global redistribution of repressive histone modifications. Functional genetic approaches show wash mutants exhibit similar phenotypes to lamin Dm0 mutants, suggesting they participate in similar regulatory networks. Our results reveal a novel role for Wash in modulating nuclear organization via its interaction with the nuclear envelope protein Lamin Dm0. These findings highlight the functional complexity of WASP family proteins and provide new venues to understand their molecular roles in cell biology and disease. DamID chromatin profiling demostrate that Wash binds similar regions to those bound by Lamin Dm0, in particular transcriptional silent chromatin

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Cellular expression of Ebola virus VP24 protein compromises the integrity of the nuclear envelope and induces a laminopathy-like cellular phenotype

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