Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding

Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding
Title:
Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding
Other Titles:
PLoS Pathogens
Keywords:
Publication Date:
06 January 2020
Citation:
Han Z, Dash S, Sagum CA, Ruthel G, Jaladanki CK, Berry CT, et al. (2020) Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding. PLoS Pathog 16(1): e1008231. https://doi.org/10.1371/journal.ppat.1008231
Abstract:
Ebola (EBOV) and Marburg (MARV) are members of the Filoviridae family, which continue to emerge and cause sporadic outbreaks of hemorrhagic fever with high mortality rates. Filoviruses utilize their VP40 matrix protein to drive virion assembly and budding, in part, by recruitment of specific WW-domain-bearing host proteins via its conserved PPxY Late (L) domain motif. Here, we screened an array of 115 mammalian, bacterially expressed and purified WW-domains using a PPxY-containing peptide from MARV VP40 (mVP40) to identify novel host interactors. Using this unbiased approach, we identified Yes Associated Protein (YAP) and Transcriptional co-Activator with PDZ-binding motif (TAZ) as novel mVP40 PPxY interactors. YAP and TAZ function as downstream transcriptional effectors of the Hippo signaling pathway that regulates cell proliferation, migration and apoptosis. We demonstrate that ectopic expression of YAP or TAZ along with mVP40 leads to significant inhibition of budding of mVP40 VLPs in a WW-domain/PPxY dependent manner. Moreover, YAP colocalized with mVP40 in the cytoplasm, and inhibition of mVP40 VLP budding was more pronounced when YAP was localized predominantly in the cytoplasm rather than in the nucleus. A key regulator of YAP nuclear/cytoplasmic localization and function is angiomotin (Amot); a multi-PPxY containing protein that strongly interacts with YAP WW-domains. Interestingly, we found that expression of PPxY-containing Amot rescued mVP40 VLP egress from either YAP- or TAZ-mediated inhibition in a PPxY-dependent manner. Importantly, using a stable Amot-knockdown cell line, we found that expression of Amot was critical for efficient egress of mVP40 VLPs as well as egress and spread of authentic MARV in infected cell cultures. In sum, we identified novel negative (YAP/TAZ) and positive (Amot) regulators of MARV VP40-mediated egress, that likely function in part, via competition between host and viral PPxY motifs binding to modular host WW-domains. These findings not only impact our mechanistic understanding of virus budding and spread, but also may impact the development of new antiviral strategies.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
Funding was provided in part by a University Research Foundation Award (Penn) and National Institutes of Health (https://www.nih.gov/) grants AI138052 and AI139392 to RNH. MS was supported by grants from the National University of Singapore (nus.edu.sg/) (R-185-000-2710-133/733), the Mechanobiology Institute (R-714-018-006-271), and IMCB (M-R02010). Probing of arrayed methyl reader domains was made possible via the UT MDACC Protein Array & Analysis Core (PAAC) CPRIT Grant RP180804 (Directed by MTB). CKJ and HF were supported by the Biomedical Research Council of A*STAR and resources of the National Supercomputing Centre, Singapore. Biosafety level-4 live virus studies were supported by Texas Biomedical Research Institute (https://www.txbiomed.org/) to OS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Description:
ISSN:
1553-7366
1553-7374
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