Dataset Information

A protein-proximity screen reveals that Ebola virus co-opts the mRNA decapping complex through the scaffold protein EDC4

ABSTRACT: Understanding the molecular interactions of host cells with Ebola virus (EBOV) is integral for further therapeutic development of antivirals. We performed a proximity-dependent protein interaction screen for six of seven EBOV proteins to characterize the EBOV-host interactome. Using network analysis, putative EBOV interacting proteins were mapped to a human protein interactome. We overlayed viral protein interactions onto the host network. Within this map, several known EBOV-host protein interactions were identified, as well as several cell processes, such as RNA processing, previously implicated in EBOV replication. Furthermore, this interactome revealed novel interactions between EBOV proteins and host proteins arranged in functional complexes. As proof of this concept, we characterized the interaction between EBOV VP35 and the mRNA decapping complex, which regulates mRNA turnover in host cells. Our protein-protein interaction data demonstrate that VP35 engages multiple components of this complex by binding binds the scaffold protein EDC4. Inhibiting expression of mRNA decapping complex components EDC4, EDC3, or DCP2 inhibited viral replication by reducing early viral RNA synthesis. Our approach examining EBOV-host protein interactions in conjunction with network analysis reveals how EBOV interacts with entire cellular machines as opposed to singular cell proteins to promote its replication.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive HF

ORGANISM(S): Ebolavirus (ncbitaxon:186536)

SUBMITTER: Douglas J. LaCount

PROVIDER: MSV000093669 | MassIVE | Thu Dec 14 08:21:00 GMT 2023

REPOSITORIES: MassIVE

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Physical interactions between viral and host proteins are responsible for almost all aspects of the viral life cycle and the host’s immune response. Studying viral-host protein-protein interactions is thus crucial for identifying strategies for treatment and prevention of viral infection. Here, we use high-throughput yeast two-hybrid and affinity purification followed by mass spectrometry to generate a comprehensive SARS-CoV-2-human protein-protein interactome network consisting of both binary and co-complex interactions. We report a total of 739 high-confidence interactions, showing the highest overlap of interaction partners among published datasets as well as the highest overlap with genes differentially expressed in samples (such as upper airway and bronchial epithelial cells) from patients with SARS-CoV-2 infection. Showcasing the utility of our network, we describe a novel interaction between the viral accessory protein ORF3a and the host zinc finger transcription factor ZNF579 to illustrate a SARS-CoV-2 factor mediating a direct impact on host transcription. Leveraging our interactome, we performed network-based drug screens for over 2,900 FDA-approved/investigational drugs and obtained a curated list of 23 drugs that had significant network proximities to SARS-CoV-2 host factors, one of which, carvedilol, showed promising antiviral properties. We performed electronic health record-based validation using two independent large-scale, longitudinal COVID-19 patient databases and found that carvedilol usage was associated with a significantly lowered probability (17%-20%, P < 0.001) of obtaining a SARS-CoV-2 positive test after adjusting various confounding factors. Carvedilol additionally showed anti-viral activity against SARS-CoV-2 in a human lung epithelial cell line [(half maximal effective concentration (EC 50 ) value of 4.1 µM]), suggesting a mechanism for its beneficial effect in COVID-19. Our study demonstrates the value of large-scale network systems biology approaches for extracting biological insight from complex biological processes.

Dataset Information

A protein-proximity screen reveals that Ebola virus co-opts the mRNA decapping complex through the scaffold protein EDC4

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets