Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding.
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-doma...
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doaj-2b5a06ea5c4348918068392abc239b3c2021-04-21T17:42:54ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742020-01-01161e100823110.1371/journal.ppat.1008231Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding.Ziying HanShantoshini DashCari A SagumGordon RuthelChaitanya K JaladankiCorbett T BerryMichael P SchwoererNina M HartyBruce D FreedmanMark T BedfordHao FanSachdev S SidhuMarius SudolOlena ShtankoRonald N HartyEbola (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.https://doi.org/10.1371/journal.ppat.1008231 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ziying Han Shantoshini Dash Cari A Sagum Gordon Ruthel Chaitanya K Jaladanki Corbett T Berry Michael P Schwoerer Nina M Harty Bruce D Freedman Mark T Bedford Hao Fan Sachdev S Sidhu Marius Sudol Olena Shtanko Ronald N Harty |
spellingShingle |
Ziying Han Shantoshini Dash Cari A Sagum Gordon Ruthel Chaitanya K Jaladanki Corbett T Berry Michael P Schwoerer Nina M Harty Bruce D Freedman Mark T Bedford Hao Fan Sachdev S Sidhu Marius Sudol Olena Shtanko Ronald N Harty Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding. PLoS Pathogens |
author_facet |
Ziying Han Shantoshini Dash Cari A Sagum Gordon Ruthel Chaitanya K Jaladanki Corbett T Berry Michael P Schwoerer Nina M Harty Bruce D Freedman Mark T Bedford Hao Fan Sachdev S Sidhu Marius Sudol Olena Shtanko Ronald N Harty |
author_sort |
Ziying Han |
title |
Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding. |
title_short |
Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding. |
title_full |
Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding. |
title_fullStr |
Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding. |
title_full_unstemmed |
Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding. |
title_sort |
modular mimicry and engagement of the hippo pathway by marburg virus vp40: implications for filovirus biology and budding. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2020-01-01 |
description |
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. |
url |
https://doi.org/10.1371/journal.ppat.1008231 |
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