Modular Mimicry and Engagement of the Hippo Pathway by Marburg Virus VP40: Implications for Filovirus Biology and Budding

Autoři: Ziying Han aff001;  Shantoshini Dash aff001;  Cari A. Sagum aff002;  Gordon Ruthel aff001;  Chaitanya K. Jaladanki aff003;  Corbett T. Berry aff001;  Michael Patrick Schwoerer aff001;  Nina M. Harty aff001;  Bruce D. Freedman aff001;  Mark T. Bedford aff002;  Hao Fan aff003;  Sachdev S. Sidhu aff004;  Marius Sudol aff003;  Olena Shtanko aff005;  Ronald N. Harty aff001
Působiště autorů: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff001;  Department of Epigenetics & Molecular Carcinogenesis, M.D. Anderson Cancer Center, University of Texas, Smithville, Texas, United States of America aff002;  Department of Physiology and Mechanobiology Institute at National University of Singapore, Institute for Molecular and Cell Biology, IMCB, and Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore aff003;  Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada aff004;  Texas Biomedical Research Institute, San Antonio, Texas, United States of America aff005
Vyšlo v časopise: Modular Mimicry and Engagement of the Hippo Pathway by Marburg Virus VP40: Implications for Filovirus Biology and Budding. PLoS Pathog 16(1): e32767. doi:10.1371/journal.ppat.1008231
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008231


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.

Klíčová slova:

Cell membranes – Cytoplasm – Graphs – Host-pathogen interactions – Membrane proteins – Phosphorylation – Protein domains – Filoviruses


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