Wesley I. Sundquist
Distinguished Professor and Chair of Biochemistry
B.A. Carleton College
Ph.D. Massachusetts Institute of Technology
Wes Sundquist's Lab Page
Wes Sundquist's PubMed Literature Search
Molecular Biology Program
Biological Chemistry Program
HIV Assembly, Replication and Restriction; Cell Division
We study the molecular and structural biology of retroviruses, with particular emphasis on the Human Immunodeficiency Virus (HIV). As summarized below, major projects in the laboratory include studies of: 1) Enveloped virus assembly, 2) ESCRT pathway functions and regulation in cell division and cancer, and 3) HIV replication and restriction. Our approaches include structural studies of viral complexes, identification and biochemical analyses of the interactions between viral components and their cellular partners, and genetic analyses of viral and cellular protein functions. We currently have active collaborations in these different areas with the University of Utah labs of Nels Elde, Chris Hill and Katie Ullman, and with Adam Frost (UCSF), Neil King (University of Washington) and Juan Martin-Serrano (Kings College, London)
Enveloped Virus Assembly
To spread infections, HIV must form enveloped spherical particles that bud through the plasma membrane. We previously showed that HIV and other retroviruses bud from cells by usurping the activity of the host ESCRT pathway (Endosomal Sorting Pathway Required for Transport). More recently, we have discovered that HIV also usurps host proteins of the Angiomotin family to facilitate membrane envelopment prior to ESCRT-mediated budding. Our current work in this area focuses on: 1) understanding the molecular mechanism of HIV assembly and budding, 2) designing and characterizing new proteins that can exit and enter cells following the principles of enveloped viruses, and 3) testing how innate immune proteins can restrict viral use of the ESCRT pathway.
ESCRT Pathway Functions in Cell Division
In addition to functioning in enveloped virus budding, the ESCRT pathway also catalyzes a variety of different cellular membrane fission reactions, including during multivesicular body biogenesis, neuronal pruning, reassembly of the post-mitotic nuclear envelope, and the final stage of cell division (termed abscission). We, and others, have shown that the ESCRT pathway mediates the final mechanical step of cytokinetic abscission, recruits and organizes a number of other activities required for abscission, and helps coordinate the abscission/NoCut checkpoint, which delays completion of abscission until mitotic processes are complete and chromosomes have cleared the intercellular bridge. These fundamental processes are essential for development and can go awry in cancer. We are currently studying how the ESCRT pathway mediates and regulates abscission, including determining: 1) the structures and functions of the constricting filaments formed by the ESCRT-III proteins, 2) how those filaments recruit other proteins and their enzymatic activities to the nascent intercellular bridge, and 3) the signaling pathways that govern the abscission checkpoint and regulate ESCRT activity.
HIV Replication and Restriction
HIV capsids facilitate reverse transcription and protect the viral genome from innate immune systems, but are also themselves the targets of host immune restriction factors. We have previously defined the structure of the HIV capsid and shown how the host restriction factor TRIM5α recognizes and assembles around the capsid. We are now studying: 1) how the capsid promotes reverse transcription, and 2) how TRIM5α binding inhibits this process.
Left: Image of a vesicle filled with designed nanocages. Right: Cryo-EM reconstruction of a single nanocage (gray) and the initial design model (green ribbons).
- McCullough J, Frost A, Sundquist WI. Structures, functions and dynamics of ESCRT-III/Vps4 Membrane remodeling and fission complexes. Annu Rev Cell Dev Biol. 2018 Oct 6;34:85-109. doi: 10.1146/annurev-cellbio-100616-060600. Epub 2018 Aug 10. PubMed PMID: 30095293. PubMed Central PMID: PMC6241870.
Schaller MD, McDowell G, Porter A, Shippen D, Friedman KL, Gentry MS, Serio TR, Sundquist WI. What's in a name? Elife. 2017 Oct 24;6. pii: e32437. doi: 10.7554/eLife.32437. PubMed PMID: 29063834; PubMed Central PMCID: PMC5655148.
Han H, Monroe N, Sundquist WI, Shen PS, Hill CP. The AAA ATPase Vps4 binds ESCRT-III substrates through a repeating array of dipeptide-binding pockets. Elife. 2017 Nov 22;6. pii: e31324. doi: 10.7554/eLife.31324. PubMed PMID: 29165244; PubMed Central PMCI
Monroe N, Han H, Shen P, Sundquist WI, Hill CP (2017). Structural basis of protein translocation by the Vps4-Vta1 AAA ATPase. eLife 6:e24487.
- Gu M, LaJoie D, Chen OS, vonAppen A, Ladinsky MS, Redd MJ, Nikolova L, Bjorkman PJ, Sundquist WI, Ullman KS, Frost A (2017). Lem2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells. Proc Natl Acad Sci 114:e2166-75.
- Votteler J, Ogohara C, Yi S, Hsia Y, Nattermann U, Belnap DM, King NP, Sundquist WI (2016). Designed proteins induce the formation of nanocage-containing extracellular vesicles. Nature 540: 292-95.
- Li YL, Chandrasekaran V, Carter SD, Woodward CL, Christensen DE, Dryden KA, Pornillos O, Yeager M, Ganser-Pornillos BK, Jensen GJ, Sundquist WI (2016). Primate TRIM5 proteins form hexagonal nets on HIV-1 capsids. eLife 5:e16269.
- Wagner JM, Roganowicz MD, Skorupka K, Alam SL, Christensen DE, Doss GL, Wan Y, Frank GA, Ganser-Pornillos BK, Sundquist WI, Pornillos O (2016). Mechanism of B-box 2 domain-mediated higher-order assembly of the retroviral restriction factor TRIM5alpha. eLife 5:e16309.
- McCullough J, Clippinger AK, Talledge N, Skowyra ML, Saunders MG, Naismith TV, Colf LA, Afonine P, Arthur C, Sundquist WI, Hanson PI, Frost A (2015). Structure and membrane remodeling activity of ESCRT-III helical polymers. Science 350:1548-51.
- Sundquist WI, Ullman KS (2015). An ESCRT to seal the envelope. Science 6241:1314-15.
- Mercenne G, Alam SL, Arii J, Lalonde MS, Sundquist WI (2015). Angiomotin functions in HIV-1 assembly and budding. eLife 4:e03778.
- Caballe A, Wenzel DM, Agromayor M, Alam SL, Skalicky JJ, Kloc M, Carlton JG, Labrador L, Sundquist WI, Martin-Serrano J (2015). ULK3 regulates cytokinetic abscission by phosphorylating ESCRT-III proteins. eLife 4:e06547.
- Pickett CL, Corbe BW, Matthews CR, Sundquist WI, Berg JM (2015). Toward a sustainable biomedical research enterprise: Finding consensus and implementing recommendations. Proc Natl Acad Sci 112:10832-6.