Membrane Complexes (Vpu, Nef)

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Vpu Project Leader: Robert Stroud

Nef Project co-Leaders: James Hurley and Matija Peterlin

Vpu is an essential, transmembrane viral protein with two main functions, namely remodeling of the cell surface to enhance viral release and modulation of NFKb signaling. By recruiting the Cul1-βTrCP-Skp1-Rbx1 (CRL1) E3 ligase complex to the membrane, Vpu promotes the re-trafficking and/or degradation of membrane proteins that can inhibit viral replication (e.g. CD4, BST-2/Tetherin, and MHC molecules). Through sequestration of βTrCP, Vpu also deregulates NFKb signaling. An additional, though less understood role of Vpu is its formation of a pentameric viroporin ion channel. To help define the multifunctional roles of Vpu and the host proteins that are related to each process, we will unite state-of-the-art proteomics discovery approaches (e.g. APEX-MS, XL-MS and PTM profiling) with targeted structural/biophysical mechanistic interrogation and novel CRISPR-based primary cell genetic validation.

Nef is essential for infectivity of virions and is now believed exert its effects primarily by downregulating the integral membrane protein SERINC3/5.  However, it is not known if Nef binds SERINCs directly or through intermediaries.  These studies are aimed at further understanding the interactions between Nef, its various partners and host factors including SERINC5, AP-2, Alix and Gag-Pol.