Investigating the interface between HIV-1 proteins and host cellular ubiquitin machinery

  • Huttenhain, Ruth R. (CoPI)
  • Krogan, Nevan (PI)

Project Details

Description

HIV relies heavily on remodeling host regulatory networks for its replication. One major target of this remodeling process is the cellular ubiquitin machinery, which modifies proteins by ubiquitin moieties to target them for degradation and to modulate their activities. HIV exploits the ubiquitination system as a means to interfere with crucial immune regulatory mechanisms in antiviral pathways and to facilitate its own propagation. Therefore, targeting the interactions between HIV proteins and the human ubiquitin machinery might be a promising direction for therapeutic intervention of HIV infection. Several viral proteins have been shown to interact with ubiquitin ligases to regulate the activity of both viral and host proteins. However, this interface remains, to a large extent uncharacterized in terms of the exact molecular composition of HIV-human ubiquitin ligase complexes, their substrates and the extended protein interaction network. Here, I propose a strategy combining quantitative mass spectrometry (MS) and computational network analysis approaches to characterize protein-protein interactions (PPIs) and ubiquitination events between HIV-1 proteins and the host ubiquitin ligases in the context of HIV-1 infection. Ubiquitin ligase-substrate relationships revealed by this strategy will be validated using a ligase trapping approach and their influence on the virus infection will be characterized by RNAi. I expect that this project will reveal new ubiquitin ligase-substrate relationships relevant for HIV-1 infection, identify specific targets for therapeutic interventions, and provide new insights into the role of the human ubiquitin machinery in immune response.

StatusActive
Effective start/end date1/01/14 → …

Funding

  • Human Frontier Science Program

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