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  1. Article ; Online: A direct RNA-protein interaction atlas of the SARS-CoV-2 RNA in infected human cells

    Schmidt, Nora / Lareau, Caleb A / Keshishian, Hasmik / Melanson, Randy / Zimmer, Matthias / Kirschner, Luisa / Ade, Jens / Werner, Simone / Caliskan, Neva / Lander, Eric S / Vogel, Joerg / Carr, Steven A / Bodem, Jochen / Munschauer, Mathias

    bioRxiv

    Abstract: SARS-CoV-2 infections pose a global threat to human health and an unprecedented research challenge. Among the most urgent tasks is obtaining a detailed understanding of the molecular interactions that facilitate viral replication or contribute to host ... ...

    Abstract SARS-CoV-2 infections pose a global threat to human health and an unprecedented research challenge. Among the most urgent tasks is obtaining a detailed understanding of the molecular interactions that facilitate viral replication or contribute to host defense mechanisms in infected cells. While SARS-CoV-2 co-opts cellular factors for viral translation and genome replication, a comprehensive map of the host cell proteome in direct contact with viral RNA has not been elucidated. Here, we use RNA antisense purification and mass spectrometry (RAP-MS) to obtain an unbiased and quantitative picture of the human proteome that directly binds the SARS-CoV-2 RNA in infected human cells. We discover known host factors required for coronavirus replication, regulators of RNA metabolism and host defense pathways, along with dozens of potential drug targets among direct SARS-CoV-2 binders. We further integrate the SARS-CoV-2 RNA interactome with proteome dynamics induced by viral infection, linking interactome proteins to the emerging biology of SARS-CoV-2 infections. Validating RAP-MS, we show that CNBP, a regulator of proinflammatory cytokines, directly engages the SARS-CoV-2 RNA. Supporting the functional relevance of identified interactors, we show that the interferon-induced protein RYDEN suppresses SARS-CoV-2 ribosomal frameshifting and demonstrate that inhibition of SARS-CoV-2-bound proteins is sufficient to manipulate viral replication. The SARS-CoV-2 RNA interactome provides an unprecedented molecular perspective on SARS-CoV-2 infections and enables the systematic dissection of host dependency factors and host defense strategies, a crucial prerequisite for designing novel therapeutic strategies.
    Keywords covid19
    Language English
    Publishing date 2020-07-15
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2020.07.15.204404
    Database COVID19

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  2. Article ; Online: A direct RNA-protein interaction atlas of the SARS-CoV-2 RNA in infected human cells

    Schmidt, Nora / Lareau, Caleb A. / Keshishian, Hasmik / Melanson, Randy / Zimmer, Matthias / Kirschner, Luisa / Ade, Jens / Werner, Simone / Caliskan, Neva / Lander, Eric S. / Vogel, Jörg / Carr, Steven A. / Bodem, Jochen / Munschauer, Mathias

    bioRxiv

    Abstract: SARS-CoV-2 infections pose a global threat to human health and an unprecedented research challenge. Among the most urgent tasks is obtaining a detailed understanding of the molecular interactions that facilitate viral replication or contribute to host ... ...

    Abstract SARS-CoV-2 infections pose a global threat to human health and an unprecedented research challenge. Among the most urgent tasks is obtaining a detailed understanding of the molecular interactions that facilitate viral replication or contribute to host defense mechanisms in infected cells. While SARS-CoV-2 co-opts cellular factors for viral translation and genome replication, a comprehensive map of the host cell proteome in direct contact with viral RNA has not been elucidated. Here, we use RNA antisense purification and mass spectrometry (RAP-MS) to obtain an unbiased and quantitative picture of the human proteome that directly binds the SARS-CoV-2 RNA in infected human cells. We discover known host factors required for coronavirus replication, regulators of RNA metabolism and host defense pathways, along with dozens of potential drug targets among direct SARS-CoV-2 binders. We further integrate the SARS-CoV-2 RNA interactome with proteome dynamics induced by viral infection, linking interactome proteins to the emerging biology of SARS-CoV-2 infections. Validating RAP-MS, we show that CNBP, a regulator of proinflammatory cytokines, directly engages the SARS-CoV-2 RNA. Supporting the functional relevance of identified interactors, we show that the interferon-induced protein RYDEN suppresses SARS-CoV-2 ribosomal frameshifting and demonstrate that inhibition of SARS-CoV-2-bound proteins is sufficient to manipulate viral replication. The SARS-CoV-2 RNA interactome provides an unprecedented molecular perspective on SARS-CoV-2 infections and enables the systematic dissection of host dependency factors and host defense strategies, a crucial prerequisite for designing novel therapeutic strategies.
    Keywords covid19
    Publisher BioRxiv; WHO
    Document type Article ; Online
    DOI 10.1101/2020.07.15.204404
    Database COVID19

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  3. Article ; Online: The SARS-CoV-2 RNA-protein interactome in infected human cells.

    Schmidt, Nora / Lareau, Caleb A / Keshishian, Hasmik / Ganskih, Sabina / Schneider, Cornelius / Hennig, Thomas / Melanson, Randy / Werner, Simone / Wei, Yuanjie / Zimmer, Matthias / Ade, Jens / Kirschner, Luisa / Zielinski, Sebastian / Dölken, Lars / Lander, Eric S / Caliskan, Neva / Fischer, Utz / Vogel, Jörg / Carr, Steven A /
    Bodem, Jochen / Munschauer, Mathias

    Nature microbiology

    2020  Volume 6, Issue 3, Page(s) 339–353

    Abstract: Characterizing the interactions that SARS-CoV-2 viral RNAs make with host cell proteins during infection can improve our understanding of viral RNA functions and the host innate immune response. Using RNA antisense purification and mass spectrometry, we ... ...

    Abstract Characterizing the interactions that SARS-CoV-2 viral RNAs make with host cell proteins during infection can improve our understanding of viral RNA functions and the host innate immune response. Using RNA antisense purification and mass spectrometry, we identified up to 104 human proteins that directly and specifically bind to SARS-CoV-2 RNAs in infected human cells. We integrated the SARS-CoV-2 RNA interactome with changes in proteome abundance induced by viral infection and linked interactome proteins to cellular pathways relevant to SARS-CoV-2 infections. We demonstrated by genetic perturbation that cellular nucleic acid-binding protein (CNBP) and La-related protein 1 (LARP1), two of the most strongly enriched viral RNA binders, restrict SARS-CoV-2 replication in infected cells and provide a global map of their direct RNA contact sites. Pharmacological inhibition of three other RNA interactome members, PPIA, ATP1A1, and the ARP2/3 complex, reduced viral replication in two human cell lines. The identification of host dependency factors and defence strategies as presented in this work will improve the design of targeted therapeutics against SARS-CoV-2.
    MeSH term(s) Autoantigens/metabolism ; COVID-19/metabolism ; COVID-19/virology ; Cell Line ; Host-Pathogen Interactions ; Humans ; Protein Interaction Maps ; Proteome ; RNA, Viral/genetics ; RNA, Viral/metabolism ; RNA-Binding Proteins/metabolism ; Ribonucleoproteins/metabolism ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; Virus Replication/physiology ; SS-B Antigen
    Chemical Substances Autoantigens ; CNBP protein, human ; Proteome ; RNA, Viral ; RNA-Binding Proteins ; Ribonucleoproteins
    Language English
    Publishing date 2020-12-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2058-5276
    ISSN (online) 2058-5276
    DOI 10.1038/s41564-020-00846-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A highly multiplexed quantitative phosphosite assay for biology and preclinical studies.

    Keshishian, Hasmik / McDonald, E Robert / Mundt, Filip / Melanson, Randy / Krug, Karsten / Porter, Dale A / Wallace, Luke / Forestier, Dominique / Rabasha, Bokang / Marlow, Sara E / Jane-Valbuena, Judit / Todres, Ellen / Specht, Harrison / Robinson, Margaret Lea / Jean Beltran, Pierre M / Babur, Ozgun / Olive, Meagan E / Golji, Javad / Kuhn, Eric /
    Burgess, Michael / MacMullan, Melanie A / Rejtar, Tomas / Wang, Karen / Mani, D R / Satpathy, Shankha / Gillette, Michael A / Sellers, William R / Carr, Steven A

    Molecular systems biology

    2021  Volume 17, Issue 9, Page(s) e10156

    Abstract: Reliable methods to quantify dynamic signaling changes across diverse pathways are needed to better understand the effects of disease and drug treatment in cells and tissues but are presently lacking. Here, we present SigPath, a targeted mass ... ...

    Abstract Reliable methods to quantify dynamic signaling changes across diverse pathways are needed to better understand the effects of disease and drug treatment in cells and tissues but are presently lacking. Here, we present SigPath, a targeted mass spectrometry (MS) assay that measures 284 phosphosites in 200 phosphoproteins of biological interest. SigPath probes a broad swath of signaling biology with high throughput and quantitative precision. We applied the assay to investigate changes in phospho-signaling in drug-treated cancer cell lines, breast cancer preclinical models, and human medulloblastoma tumors. In addition to validating previous findings, SigPath detected and quantified a large number of differentially regulated phosphosites newly associated with disease models and human tumors at baseline or with drug perturbation. Our results highlight the potential of SigPath to monitor phosphoproteomic signaling events and to nominate mechanistic hypotheses regarding oncogenesis, response, and resistance to therapy.
    MeSH term(s) Humans ; Mass Spectrometry ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Phosphorylation ; Proteomics ; Signal Transduction
    Chemical Substances Phosphoproteins
    Language English
    Publishing date 2021-09-27
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2193510-5
    ISSN 1744-4292 ; 1744-4292
    ISSN (online) 1744-4292
    ISSN 1744-4292
    DOI 10.15252/msb.202010156
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation.

    Khadka, Prasidda / Reitman, Zachary J / Lu, Sophie / Buchan, Graham / Gionet, Gabrielle / Dubois, Frank / Carvalho, Diana M / Shih, Juliann / Zhang, Shu / Greenwald, Noah F / Zack, Travis / Shapira, Ofer / Pelton, Kristine / Hartley, Rachel / Bear, Heather / Georgis, Yohanna / Jarmale, Spandana / Melanson, Randy / Bonanno, Kevin /
    Schoolcraft, Kathleen / Miller, Peter G / Condurat, Alexandra L / Gonzalez, Elizabeth M / Qian, Kenin / Morin, Eric / Langhnoja, Jaldeep / Lupien, Leslie E / Rendo, Veronica / Digiacomo, Jeromy / Wang, Dayle / Zhou, Kevin / Kumbhani, Rushil / Guerra Garcia, Maria E / Sinai, Claire E / Becker, Sarah / Schneider, Rachel / Vogelzang, Jayne / Krug, Karsten / Goodale, Amy / Abid, Tanaz / Kalani, Zohra / Piccioni, Federica / Beroukhim, Rameen / Persky, Nicole S / Root, David E / Carcaboso, Angel M / Ebert, Benjamin L / Fuller, Christine / Babur, Ozgun / Kieran, Mark W / Jones, Chris / Keshishian, Hasmik / Ligon, Keith L / Carr, Steven A / Phoenix, Timothy N / Bandopadhayay, Pratiti

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 604

    Abstract: The role of PPM1D mutations in de novo gliomagenesis has not been systematically explored. Here we analyze whole genome sequences of 170 pediatric high-grade gliomas and find that truncating mutations in PPM1D that increase the stability of its ... ...

    Abstract The role of PPM1D mutations in de novo gliomagenesis has not been systematically explored. Here we analyze whole genome sequences of 170 pediatric high-grade gliomas and find that truncating mutations in PPM1D that increase the stability of its phosphatase are clonal driver events in 11% of Diffuse Midline Gliomas (DMGs) and are enriched in primary pontine tumors. Through the development of DMG mouse models, we show that PPM1D mutations potentiate gliomagenesis and that PPM1D phosphatase activity is required for in vivo oncogenesis. Finally, we apply integrative phosphoproteomic and functional genomics assays and find that oncogenic effects of PPM1D truncation converge on regulators of cell cycle, DNA damage response, and p53 pathways, revealing therapeutic vulnerabilities including MDM2 inhibition.
    MeSH term(s) Adolescent ; Adult ; Animals ; Brain Stem Neoplasms/genetics ; Carcinogenesis/genetics ; Cell Cycle ; Child ; Child, Preschool ; DNA Damage ; Disease Models, Animal ; Female ; Glioma/genetics ; HEK293 Cells ; Humans ; Infant ; Male ; Mice ; Mutation ; Oncogenes/genetics ; Protein Phosphatase 2C/genetics ; Proto-Oncogene Proteins c-mdm2 ; Transcriptome ; Tumor Suppressor Protein p53/genetics ; Young Adult
    Chemical Substances Tumor Suppressor Protein p53 ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; PPM1D protein, human (EC 3.1.3.16) ; Protein Phosphatase 2C (EC 3.1.3.16)
    Language English
    Publishing date 2022-02-01
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-28198-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: The SARS-CoV-2 RNA-protein interactome in infected human cells.

    Schmidt, Nora / Lareau, Caleb A / Keshishian, Hasmik / Ganskih, Sabina / Schneider, Cornelius / Hennig, Thomas / Melanson, Randy / Werner, Simone / Wei, Yuanjie / Zimmer, Matthias / Ade, Jens / Kirschner, Luisa / Zielinski, Sebastian / Dölken, Lars / Lander, Eric S / Caliskan, Neva / Fischer, Utz / Vogel, Jörg / Carr, Steven A /
    Bodem, Jochen / Munschauer, Mathias

    Nature microbiology ; England

    2020  

    Abstract: Characterizing the interactions that SARS-CoV-2 viral RNAs make with host cell proteins during infection can improve our understanding of viral RNA functions and the host innate immune response. Using RNA antisense purification and mass spectrometry, we ... ...

    Abstract Characterizing the interactions that SARS-CoV-2 viral RNAs make with host cell proteins during infection can improve our understanding of viral RNA functions and the host innate immune response. Using RNA antisense purification and mass spectrometry, we identified up to 104 human proteins that directly and specifically bind to SARS-CoV-2 RNAs in infected human cells. We integrated the SARS-CoV-2 RNA interactome with changes in proteome abundance induced by viral infection and linked interactome proteins to cellular pathways relevant to SARS-CoV-2 infections. We demonstrated by genetic perturbation that cellular nucleic acid-binding protein (CNBP) and La-related protein 1 (LARP1), two of the most strongly enriched viral RNA binders, restrict SARS-CoV-2 replication in infected cells and provide a global map of their direct RNA contact sites. Pharmacological inhibition of three other RNA interactome members, PPIA, ATP1A1, and the ARP2/3 complex, reduced viral replication in two human cell lines. The identification of host dependency factors and defence strategies as presented in this work will improve the design of targeted therapeutics against SARS-CoV-2.
    Subject code 570
    Language English
    Publishing date 2020-12-21
    Publisher Nature research
    Publishing country de
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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