دورية أكاديمية
Hippo signaling pathway regulates Ebola virus transcription and egress.
العنوان: | Hippo signaling pathway regulates Ebola virus transcription and egress. |
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المؤلفون: | Liang J; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA, 19104, USA., Djurkovic MA; Host-Pathogen Interactions, Texas Biomedical Research Institute, 8715 W. Military Drive, San Antonio, TX, 78227, USA., Leavitt CG; Host-Pathogen Interactions, Texas Biomedical Research Institute, 8715 W. Military Drive, San Antonio, TX, 78227, USA., Shtanko O; Host-Pathogen Interactions, Texas Biomedical Research Institute, 8715 W. Military Drive, San Antonio, TX, 78227, USA. oshtanko@txbiomed.org., Harty RN; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA, 19104, USA. rharty@vet.upenn.edu. |
المصدر: | Nature communications [Nat Commun] 2024 Aug 13; Vol. 15 (1), pp. 6953. Date of Electronic Publication: 2024 Aug 13. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: [London] : Nature Pub. Group |
مواضيع طبية MeSH: | Protein Serine-Threonine Kinases*/metabolism , Protein Serine-Threonine Kinases*/genetics , Hippo Signaling Pathway* , Signal Transduction* , Ebolavirus*/physiology , Ebolavirus*/genetics , Ebolavirus*/metabolism , Virus Release* , Transcription Factors*/metabolism , Transcription Factors*/genetics , Transcription, Genetic*, Humans ; Phosphorylation ; HEK293 Cells ; Tumor Suppressor Proteins/metabolism ; Tumor Suppressor Proteins/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Adaptor Proteins, Signal Transducing/genetics ; YAP-Signaling Proteins/metabolism ; Viral Matrix Proteins/metabolism ; Viral Matrix Proteins/genetics ; Hemorrhagic Fever, Ebola/virology ; Hemorrhagic Fever, Ebola/metabolism ; Host-Pathogen Interactions ; Cell Cycle Proteins/metabolism ; Cell Cycle Proteins/genetics |
مستخلص: | Filovirus-host interactions play important roles in all stages of the virus lifecycle. Here, we identify LATS1/2 kinases and YAP, key components of the Hippo pathway, as critical regulators of EBOV transcription and egress. Specifically, we find that when YAP is phosphorylated by LATS1/2, it localizes to the cytoplasm (Hippo "ON") where it sequesters VP40 to prevent egress. In contrast, when the Hippo pathway is "OFF", unphosphorylated YAP translocates to the nucleus where it transcriptionally activates host genes and promotes viral egress. Our data reveal that LATS2 indirectly modulates filoviral VP40-mediated egress through phosphorylation of AMOTp130, a positive regulator of viral egress, but more surprisingly that LATS1/2 kinases directly modulate EBOV transcription by phosphorylating VP30, an essential regulator of viral transcription. In sum, our findings highlight the potential to exploit the Hippo pathway/filovirus axis for the development of host-oriented countermeasures targeting EBOV and related filoviruses. (© 2024. The Author(s).) |
References: | Subissi, L. et al. Ebola virus transmission caused by persistently infected survivors of the 2014-2016 outbreak in West Africa. J. Infect. Dis. 218, S287–s291 (2018). (PMID: 10.1093/infdis/jiy280299206026249578) Coffin, K. M. et al. Persistent Marburg virus infection in the testes of nonhuman primate survivors. Cell Host Microbe 24, 405–416.e403 (2018). (PMID: 10.1016/j.chom.2018.08.00330173956) Hoenen, T., Groseth, A. & Feldmann, H. Therapeutic strategies to target the Ebola virus life cycle. Nat. Rev. Microbiol. 17, 593–606 (2019). (PMID: 10.1038/s41579-019-0233-231341272) Jacob, S. T. et al. Ebola virus disease. Nat. Rev. Dis. Primers 6, 13 (2020). (PMID: 10.1038/s41572-020-0147-3320801997223853) Bodmer, B. S., Hoenen, T. & Wendt, L. Molecular insights into the Ebola virus life cycle. Nat. Microbiol. https://doi.org/10.1038/s41564-024-01703-z (2024). Harty, R. N., Brown, M. E., Wang, G., Huibregtse, J. & Hayes, F. P. A PPxY motif within the VP40 protein of Ebola virus interacts physically and functionally with a ubiquitin ligase: implications for filovirus budding. Proc. Natl Acad. Sci. USA 97, 13871–13876 (2000). (PMID: 10.1073/pnas.2502772971109572417668) Han, Z. et al. ITCH E3 ubiquitin ligase interacts with Ebola virus VP40 to regulate budding. J. Virol. 90, 9163–9171 (2016). (PMID: 10.1128/JVI.01078-16274892725044852) Han, Z. et al. Ubiquitin ligase WWP1 interacts with Ebola virus VP40 to regulate egress. J. Virol. https://doi.org/10.1128/jvi.00812-17 (2017). Liang, J. et al. Chaperone-mediated autophagy protein BAG3 negatively regulates Ebola and Marburg VP40-mediated egress. PLoS Pathog. 13, e1006132 (2017). (PMID: 10.1371/journal.ppat.1006132280764205226679) Liang, J. et al. Angiomotin counteracts the negative regulatory effect of host WWOX on viral PPxY-mediated egress. J. Virol. https://doi.org/10.1128/jvi.00121-21 (2021). Liang, J., Ruthel, G., Freedman, B. D. & Harty, R. N. WWOX-mediated degradation of AMOTp130 negatively affects egress of filovirus VP40 virus-like particles. J. Virol. 96, e0202621 (2022). (PMID: 10.1128/jvi.02026-2135107375) Liang, J., Djurkovic, M. A., Shtanko, O. & Harty, R. N. Chaperone-assisted selective autophagy targets filovirus VP40 as a client and restricts egress of virus particles. Proc. Natl Acad. Sci. USA 120, e2210690120 (2023). (PMID: 10.1073/pnas.2210690120365989509926251) Han, Z. et al. Angiomotin regulates budding and spread of Ebola virus. J. Biol. Chem. 295, 8596–8601 (2020). (PMID: 10.1074/jbc.AC120.013171323815097307192) Han, Z. et al. Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding. PLoS Pathog. 16, e1008231 (2020). (PMID: 10.1371/journal.ppat.1008231319052276977764) Hansen, C. G., Moroishi, T. & Guan, K. L. YAP and TAZ: a nexus for Hippo signaling and beyond. Trends Cell Biol. 25, 499–513 (2015). (PMID: 10.1016/j.tcb.2015.05.002260452584554827) Meng, Z., Moroishi, T. & Guan, K. L. Mechanisms of Hippo pathway regulation. Genes Dev. 30, 1–17 (2016). (PMID: 10.1101/gad.274027.115267285534701972) Ma, S., Meng, Z., Chen, R. & Guan, K. L. The Hippo pathway: biology and pathophysiology. Ann. Rev. Biochem. 88, 577–604 (2019). (PMID: 10.1146/annurev-biochem-013118-11182930566373) Yu, F. X. & Guan, K. L. The Hippo pathway: regulators and regulations. Genes Dev. 27, 355–371 (2013). (PMID: 10.1101/gad.210773.112234310533589553) Zhao, B. et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 21, 2747–2761 (2007). (PMID: 10.1101/gad.1602907179749162045129) Zhao, B., Li, L., Tumaneng, K., Wang, C. Y. & Guan, K. L. A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev. 24, 72–85 (2010). (PMID: 10.1101/gad.1843810200480012802193) Oka, T., Mazack, V. & Sudol, M. Mst2 and Lats kinases regulate apoptotic function of Yes kinase-associated protein (YAP). J. Biol. Chem. 283, 27534–27546 (2008). (PMID: 10.1074/jbc.M80438020018640976) Plouffe, S. W. et al. The Hippo pathway effector proteins YAP and TAZ have both distinct and overlapping functions in the cell. J. Biol. Chem. 293, 11230–11240 (2018). (PMID: 10.1074/jbc.RA118.002715298022016052207) Totaro, A., Panciera, T. & Piccolo, S. YAP/TAZ upstream signals and downstream responses. Nat. Cell Biol. 20, 888–899 (2018). (PMID: 10.1038/s41556-018-0142-z300501196186418) King, B., Araki, J., Palm, W. & Thompson, C. B. Yap/Taz promote the scavenging of extracellular nutrients through macropinocytosis. Genes Dev. 34, 1345–1358 (2020). (PMID: 10.1101/gad.340661.120329129027528706) Shimojima, M., Ikeda, Y. & Kawaoka, Y. The mechanism of Axl-mediated Ebola virus infection. J. Infect. Dis. 196, S259–S263 (2007). (PMID: 10.1086/52059417940958) Hunt, C. L., Kolokoltsov, A. A., Davey, R. A. & Maury, W. The Tyro3 receptor kinase Axl enhances macropinocytosis of Zaire ebolavirus. J. Virol. 85, 334–347 (2011). (PMID: 10.1128/JVI.01278-0921047970) Nanbo, A. et al. Ebolavirus is internalized into host cells via macropinocytosis in a viral glycoprotein-dependent manner. PLoS Pathog. 6, e1001121 (2010). (PMID: 10.1371/journal.ppat.1001121208861082944813) Cureton, D. K., Massol, R. H., Saffarian, S., Kirchhausen, T. L. & Whelan, S. P. Vesicular stomatitis virus enters cells through vesicles incompletely coated with clathrin that depend upon actin for internalization. PLoS Pathog. 5, e1000394 (2009). (PMID: 10.1371/journal.ppat.1000394193906042667253) Fan, R., Kim, N. G. & Gumbiner, B. M. Regulation of Hippo pathway by mitogenic growth factors via phosphoinositide 3-kinase and phosphoinositide-dependent kinase-1. Proc. Natl Acad. Sci. USA 110, 2569–2574 (2013). (PMID: 10.1073/pnas.1216462110233596933574943) Liu-Chittenden, Y. et al. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 26, 1300–1305 (2012). (PMID: 10.1101/gad.192856.112226775473387657) Wang, C. et al. Verteporfin inhibits YAP function through up-regulating 14-3-3σ sequestering YAP in the cytoplasm. Am. J. Cancer Res. 6, 27–37 (2016). (PMID: 27073720) Wynne, J. W. et al. Comparative transcriptomics highlights the role of the activator protein 1 transcription factor in the host response to Ebolavirus. J. Virol. https://doi.org/10.1128/jvi.01174-17 (2017). Zeng, X. et al. Identification and pathological characterization of persistent asymptomatic Ebola virus infection in rhesus monkeys. Nat. Microbiol. 2, 17113 (2017). (PMID: 10.1038/nmicrobiol.2017.11328715405) Martines, R. B., Ng, D. L., Greer, P. W., Rollin, P. E. & Zaki, S. R. Tissue and cellular tropism, pathology and pathogenesis of Ebola and Marburg viruses. J. Pathol. 235, 153–174 (2015). (PMID: 10.1002/path.445625297522) Chan, S. W. et al. Actin-binding and cell proliferation activities of angiomotin family members are regulated by Hippo pathway-mediated phosphorylation. J. Biol. Chem. 288, 37296–37307 (2013). (PMID: 10.1074/jbc.M113.527598242259523873582) Dai, X. et al. Phosphorylation of angiomotin by Lats1/2 kinases inhibits F-actin binding, cell migration, and angiogenesis. J. Biol. Chem. 288, 34041–34051 (2013). (PMID: 10.1074/jbc.M113.518019241062673837143) Meng, Z. et al. MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway. Nat. Commun. 6, 8357 (2015). (PMID: 10.1038/ncomms935726437443) Wang, L. et al. Multiphase coalescence mediates Hippo pathway activation. Cell 185, 4376–4393.e4318 (2022). (PMID: 10.1016/j.cell.2022.09.036363189209669202) Nelson, E. V. et al. An RNA polymerase II-driven Ebola virus minigenome system as an advanced tool for antiviral drug screening. Antiviral Res. 146, 21–27 (2017). (PMID: 10.1016/j.antiviral.2017.08.005288076855654650) Takamatsu, Y. et al. Serine-arginine protein kinase 1 regulates Ebola virus transcription. mBio https://doi.org/10.1128/mBio.02565-19 (2020). Lier, C., Becker, S. & Biedenkopf, N. Dynamic phosphorylation of Ebola virus VP30 in NP-induced inclusion bodies. Virology 512, 39–47 (2017). (PMID: 10.1016/j.virol.2017.09.00628915404) Biedenkopf, N., Lier, C. & Becker, S. Dynamic phosphorylation of VP30 is essential for Ebola virus life cycle. J. Virol. 90, 4914–4925 (2016). (PMID: 10.1128/JVI.03257-15269370284859730) Hoenen, T. et al. Inclusion bodies are a site of Ebolavirus replication. J. Virol. 86, 11779–11788 (2012). (PMID: 10.1128/JVI.01525-12229158103486333) Kastan, N. R. et al. Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs. Proc. Natl. Acad. Sci. USA 119, e2206113119 (2022). (PMID: 10.1073/pnas.2206113119358677649282237) Yaron, T. M. et al. Host protein kinases required for SARS-CoV-2 nucleocapsid phosphorylation and viral replication. Sci. Signal. 15, eabm0808 (2022). (PMID: 10.1126/scisignal.abm0808362829119830954) Monteil, V. et al. Identification of CCZ1 as an essential lysosomal trafficking regulator in Marburg and Ebola virus infections. Nat. Commun. 14, 6785 (2023). (PMID: 10.1038/s41467-023-42526-63788024710600203) Muñoz-Wolf, N. & Lavelle, E. C. Hippo interferes with antiviral defences. Nat. Cell Biol. 19, 267–269 (2017). (PMID: 10.1038/ncb350228361938) Zhang, Q. et al. Hippo signalling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade. Nat. Cell Biol. 19, 362–374 (2017). (PMID: 10.1038/ncb3496283464395398908) Garcia, G. Jr. et al. Hippo signaling pathway has a critical role in Zika virus replication and in the pathogenesis of neuroinflammation. Am. J. Pathol. 190, 844–861 (2020). (PMID: 10.1016/j.ajpath.2019.12.005320350587163250) Garcia, G. Jr. et al. Hippo signaling pathway activation during SARS-CoV-2 infection contributes to host antiviral response. PLoS Biol. 20, e3001851 (2022). (PMID: 10.1371/journal.pbio.3001851363467809642871) Shepley-McTaggart, A. et al. Contrasting effects of filamin A and B proteins in modulating filovirus entry. PLoS Pathog. 19, e1011595 (2023). (PMID: 10.1371/journal.ppat.10115953758547810461817) Wang, X. et al. YAP/TAZ orchestrate VEGF signaling during developmental angiogenesis. Dev. Cell 42, 462–478.e467 (2017). (PMID: 10.1016/j.devcel.2017.08.00228867486) Kindrachuk, J. et al. Ebola virus modulates transforming growth factor β signaling and cellular markers of mesenchyme-like transition in hepatocytes. J. Virol. 88, 9877–9892 (2014). (PMID: 10.1128/JVI.01410-14249425694136307) Gao, J. et al. Ebola virus disrupts the inner blood-retinal barrier by induction of vascular endothelial growth factor in pericytes. PLoS Pathog. 19, e1011077 (2023). (PMID: 10.1371/journal.ppat.1011077366524439847965) Smoot, R. L. et al. Platelet-derived growth factor regulates YAP transcriptional activity via Src family kinase dependent tyrosine phosphorylation. J. Cell. Biochem. 119, 824–836 (2018). (PMID: 10.1002/jcb.2624628661054) Furth, N. & Aylon, Y. The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway. Cell Death Differ. 24, 1488–1501 (2017). (PMID: 10.1038/cdd.2017.99286444365563998) Tang, F. et al. LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function. Nat. Commun. 10, 5755 (2019). (PMID: 10.1038/s41467-019-13591-7318483406917744) Martinez, M. J. et al. Role of VP30 phosphorylation in the Ebola virus replication cycle. J. Infect. Dis. 204, S934–S940 (2011). (PMID: 10.1093/infdis/jir32021987772) Biedenkopf, N., Hartlieb, B., Hoenen, T. & Becker, S. Phosphorylation of Ebola virus VP30 influences the composition of the viral nucleocapsid complex: impact on viral transcription and replication. J. Biol. Chem. 288, 11165–11174 (2013). (PMID: 10.1074/jbc.M113.461285234933933630872) Brauburger, K., Deflubé, L. R. & Mühlberger, E. in Biology and Pathogenesis of Rhabdo- and Filoviruses (eds. Pattnaik, A. K. & Whitt, M. K.) Chapter #20, (World Scientific, 2014). Takamatsu, Y. et al. Role of VP30 phosphorylation in Ebola virus nucleocapsid assembly and transport. J. Virol. 96, e0108322 (2022). (PMID: 10.1128/jvi.01083-2235993739) Batra, J. et al. Non-canonical proline-tyrosine interactions with multiple host proteins regulate Ebola virus infection. EMBO J. 40, e105658 (2021). (PMID: 10.15252/embj.2020105658342600768441301) Kolesnikova, L., Nanbo, A., Becker, S. & Kawaoka, Y. in Marburg- and Ebolaviruses: From Ecosystems to Molecules (eds Mühlberger, E., Hensley, L. L. & Towner, J. S.) (Springer International Publishing, 2017). Ilinykh, P. A. et al. Role of protein phosphatase 1 in dephosphorylation of Ebola virus VP30 protein and its targeting for the inhibition of viral transcription. J. Biol. Chem. 289, 22723–22738 (2014). (PMID: 10.1074/jbc.M114.575050249360584132779) Kruse, T. et al. The Ebola virus nucleoprotein recruits the host PP2A-B56 phosphatase to activate transcriptional support activity of VP30. Mol. Cell 69, 136–145.e136 (2018). (PMID: 10.1016/j.molcel.2017.11.03429290611) Ahmad, A. et al. Ebola virus NP binding to host protein phosphatase-1 regulates capsid formation. Res. Sq. https://doi.org/10.21203/rs.3.rs-2963943/v1 (2023). Licata, J. M. et al. Overlapping motifs (PTAP and PPEY) within the Ebola virus VP40 protein function independently as late budding domains: involvement of host proteins TSG101 and VPS-4. J. Virol. 77, 1812–1819 (2003). (PMID: 10.1128/JVI.77.3.1812-1819.200312525615140960) Shtanko, O. et al. Retro-2 and its dihydroquinazolinone derivatives inhibit filovirus infection. Antiviral Res. 149, 154–163 (2018). (PMID: 10.1016/j.antiviral.2017.11.01629175127) Fernandez, M., Porosnicu, M., Markovic, D. & Barber, G. N. Genetically engineered vesicular stomatitis virus in gene therapy: application for treatment of malignant disease. J. Virol. 76, 895–904 (2002). (PMID: 10.1128/JVI.76.2.895-904.200211752178136833) McCarthy, S. E., Johnson, R. F., Zhang, Y. A., Sunyer, J. O. & Harty, R. N. Role for amino acids 212KLR214 of Ebola virus VP40 in assembly and budding. J. Virol. 81, 11452–11460 (2007). (PMID: 10.1128/JVI.00853-07176995762045517) Miller, M. E., Adhikary, S., Kolokoltsov, A. A. & Davey, R. A. Ebolavirus requires acid sphingomyelinase activity and plasma membrane sphingomyelin for infection. J. Virol. 86, 7473–7483 (2012). (PMID: 10.1128/JVI.00136-12225738583416309) Rogers, K. J. et al. Frontline science: CD40 signaling restricts RNA virus replication in Mϕs, leading to rapid innate immune control of acute virus infection. J. Leukoc. Biol. 109, 309–325 (2021). (PMID: 10.1002/JLB.4HI0420-285RR32441445) |
معلومات مُعتمدة: | AI151717 U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID); AI153815 U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID); AI139392 U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID); AI154336 U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID); R21 AI151717 United States AI NIAID NIH HHS; R21 AI139392 United States AI NIAID NIH HHS; R21 AI153815 United States AI NIAID NIH HHS; AI138052 U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID); R21 AI138052 United States AI NIAID NIH HHS; R21 AI154336 United States AI NIAID NIH HHS |
المشرفين على المادة: | EC 2.7.11.1 (Protein Serine-Threonine Kinases) EC 2.7.1.- (LATS1 protein, human) 0 (Transcription Factors) EC 2.7.1.11 (LATS2 protein, human) 0 (Tumor Suppressor Proteins) 0 (Adaptor Proteins, Signal Transducing) 0 (YAP-Signaling Proteins) 0 (Viral Matrix Proteins) 0 (VP40 protein, virus) 0 (YAP1 protein, human) 0 (Cell Cycle Proteins) |
تواريخ الأحداث: | Date Created: 20240813 Date Completed: 20240813 Latest Revision: 20240816 |
رمز التحديث: | 20240817 |
مُعرف محوري في PubMed: | PMC11322314 |
DOI: | 10.1038/s41467-024-51356-z |
PMID: | 39138205 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2041-1723 |
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DOI: | 10.1038/s41467-024-51356-z |