Protein Interaction Mapping Identifies RBBP6 as a Negative Regulator of Ebola Virus Replication

Jyoti Batra; Judd F. Hultquist; Dandan Liu; Olena Shtanko; John Von Dollen; Laura Satkamp; Gwendolyn M. Jang; Priya Luthra; Toni M. Schwarz; Gabriel I. Small; Eusondia Arnett; Manu Anantpadma; Ann Reyes; Daisy W. Leung; Robyn Kaake; Paige Haas; Carson B. Schmidt; Larry S. Schlesinger; Douglas J. LaCount; Robert A. Davey; Gaya K. Amarasinghe; Christopher F. Basler; Nevan J. Krogan

doi:10.1016/j.cell.2018.08.044

Protein Interaction Mapping Identifies RBBP6 as a Negative Regulator of Ebola Virus Replication

Jyoti Batra, Judd F. Hultquist, Dandan Liu, Olena Shtanko, John Von Dollen, Laura Satkamp, Gwendolyn M. Jang, Priya Luthra, Toni M. Schwarz, Gabriel I. Small, Eusondia Arnett, Manu Anantpadma, Ann Reyes, Daisy W. Leung, Robyn Kaake, Paige Haas, Carson B. Schmidt, Larry S. Schlesinger, Douglas J. LaCount, Robert A. DaveyGaya K. Amarasinghe, Christopher F. Basler^*, Nevan J. Krogan

^*Corresponding author for this work

Medicine, Infectious Diseases Division

Research output: Contribution to journal › Article › peer-review

100 Scopus citations

Abstract

Ebola virus (EBOV) infection often results in fatal illness in humans, yet little is known about how EBOV usurps host pathways during infection. To address this, we used affinity tag-purification mass spectrometry (AP-MS) to generate an EBOV-host protein-protein interaction (PPI) map. We uncovered 194 high-confidence EBOV-human PPIs, including one between the viral transcription regulator VP30 and the host ubiquitin ligase RBBP6. Domain mapping identified a 23 amino acid region within RBBP6 that binds to VP30. A crystal structure of the VP30-RBBP6 peptide complex revealed that RBBP6 mimics the viral nucleoprotein (NP) binding to the same interface of VP30. Knockdown of endogenous RBBP6 stimulated viral transcription and increased EBOV replication, whereas overexpression of either RBBP6 or the peptide strongly inhibited both. These results demonstrate the therapeutic potential of biologics that target this interface and identify additional PPIs that may be leveraged for novel therapeutic strategies. A host-Ebola protein-protein interaction map identifies candidate drug targets, including a host ubiquitin ligase that prevents viral replication, peptide mimics of which strongly inhibit Ebola replication in multiple cell types.

Original language	English (US)
Pages (from-to)	1917-1930.e13
Journal	Cell
Volume	175
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2018.08.044
State	Published - Dec 13 2018

Keywords

Ebola virus
RBBP6
RNA viruses
VP30
antiviral factor
host-pathogen interactions
protein-protein interactions
virus-host interactions

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2018.08.044

Cite this

Batra, J., Hultquist, J. F., Liu, D., Shtanko, O., Von Dollen, J., Satkamp, L., Jang, G. M., Luthra, P., Schwarz, T. M., Small, G. I., Arnett, E., Anantpadma, M., Reyes, A., Leung, D. W., Kaake, R., Haas, P., Schmidt, C. B., Schlesinger, L. S., LaCount, D. J., ... Krogan, N. J. (2018). Protein Interaction Mapping Identifies RBBP6 as a Negative Regulator of Ebola Virus Replication. Cell, 175(7), 1917-1930.e13. https://doi.org/10.1016/j.cell.2018.08.044

@article{f8c5ce22278d43948ec269eb0e1a79cb,

title = "Protein Interaction Mapping Identifies RBBP6 as a Negative Regulator of Ebola Virus Replication",

abstract = "Ebola virus (EBOV) infection often results in fatal illness in humans, yet little is known about how EBOV usurps host pathways during infection. To address this, we used affinity tag-purification mass spectrometry (AP-MS) to generate an EBOV-host protein-protein interaction (PPI) map. We uncovered 194 high-confidence EBOV-human PPIs, including one between the viral transcription regulator VP30 and the host ubiquitin ligase RBBP6. Domain mapping identified a 23 amino acid region within RBBP6 that binds to VP30. A crystal structure of the VP30-RBBP6 peptide complex revealed that RBBP6 mimics the viral nucleoprotein (NP) binding to the same interface of VP30. Knockdown of endogenous RBBP6 stimulated viral transcription and increased EBOV replication, whereas overexpression of either RBBP6 or the peptide strongly inhibited both. These results demonstrate the therapeutic potential of biologics that target this interface and identify additional PPIs that may be leveraged for novel therapeutic strategies. A host-Ebola protein-protein interaction map identifies candidate drug targets, including a host ubiquitin ligase that prevents viral replication, peptide mimics of which strongly inhibit Ebola replication in multiple cell types.",

keywords = "Ebola virus, RBBP6, RNA viruses, VP30, antiviral factor, host-pathogen interactions, protein-protein interactions, virus-host interactions",

author = "Jyoti Batra and Hultquist, {Judd F.} and Dandan Liu and Olena Shtanko and {Von Dollen}, John and Laura Satkamp and Jang, {Gwendolyn M.} and Priya Luthra and Schwarz, {Toni M.} and Small, {Gabriel I.} and Eusondia Arnett and Manu Anantpadma and Ann Reyes and Leung, {Daisy W.} and Robyn Kaake and Paige Haas and Schmidt, {Carson B.} and Schlesinger, {Larry S.} and LaCount, {Douglas J.} and Davey, {Robert A.} and Amarasinghe, {Gaya K.} and Basler, {Christopher F.} and Krogan, {Nevan J.}",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = dec,

day = "13",

doi = "10.1016/j.cell.2018.08.044",

language = "English (US)",

volume = "175",

pages = "1917--1930.e13",

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Batra, J, Hultquist, JF, Liu, D, Shtanko, O, Von Dollen, J, Satkamp, L, Jang, GM, Luthra, P, Schwarz, TM, Small, GI, Arnett, E, Anantpadma, M, Reyes, A, Leung, DW, Kaake, R, Haas, P, Schmidt, CB, Schlesinger, LS, LaCount, DJ, Davey, RA, Amarasinghe, GK, Basler, CF & Krogan, NJ 2018, 'Protein Interaction Mapping Identifies RBBP6 as a Negative Regulator of Ebola Virus Replication', Cell, vol. 175, no. 7, pp. 1917-1930.e13. https://doi.org/10.1016/j.cell.2018.08.044

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T1 - Protein Interaction Mapping Identifies RBBP6 as a Negative Regulator of Ebola Virus Replication

AU - Batra, Jyoti

AU - Hultquist, Judd F.

AU - Liu, Dandan

AU - Shtanko, Olena

AU - Von Dollen, John

AU - Satkamp, Laura

AU - Jang, Gwendolyn M.

AU - Luthra, Priya

AU - Schwarz, Toni M.

AU - Small, Gabriel I.

AU - Arnett, Eusondia

AU - Anantpadma, Manu

AU - Reyes, Ann

AU - Leung, Daisy W.

AU - Kaake, Robyn

AU - Haas, Paige

AU - Schmidt, Carson B.

AU - Schlesinger, Larry S.

AU - LaCount, Douglas J.

AU - Davey, Robert A.

AU - Amarasinghe, Gaya K.

AU - Basler, Christopher F.

AU - Krogan, Nevan J.

PY - 2018/12/13

Y1 - 2018/12/13

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AB - Ebola virus (EBOV) infection often results in fatal illness in humans, yet little is known about how EBOV usurps host pathways during infection. To address this, we used affinity tag-purification mass spectrometry (AP-MS) to generate an EBOV-host protein-protein interaction (PPI) map. We uncovered 194 high-confidence EBOV-human PPIs, including one between the viral transcription regulator VP30 and the host ubiquitin ligase RBBP6. Domain mapping identified a 23 amino acid region within RBBP6 that binds to VP30. A crystal structure of the VP30-RBBP6 peptide complex revealed that RBBP6 mimics the viral nucleoprotein (NP) binding to the same interface of VP30. Knockdown of endogenous RBBP6 stimulated viral transcription and increased EBOV replication, whereas overexpression of either RBBP6 or the peptide strongly inhibited both. These results demonstrate the therapeutic potential of biologics that target this interface and identify additional PPIs that may be leveraged for novel therapeutic strategies. A host-Ebola protein-protein interaction map identifies candidate drug targets, including a host ubiquitin ligase that prevents viral replication, peptide mimics of which strongly inhibit Ebola replication in multiple cell types.

KW - Ebola virus

KW - RBBP6

KW - RNA viruses

KW - VP30

KW - antiviral factor

KW - host-pathogen interactions

KW - protein-protein interactions

KW - virus-host interactions

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SN - 0092-8674

VL - 175

SP - 1917-1930.e13

JO - Cell

JF - Cell

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Protein Interaction Mapping Identifies RBBP6 as a Negative Regulator of Ebola Virus Replication

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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Crystal structure of Ebola virus VP30 C-terminus/RBBP6 peptide complex

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Protein Interaction Mapping Identifies RBBP6 as a Negative Regulator of Ebola Virus Replication

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Datasets

Crystal structure of Ebola virus VP30 C-terminus/RBBP6 peptide complex

Cite this