Wesley Sundquist

To leave a cell and spread infection, HIV viral particles must become enveloped within a membrane and bud from the cell. Sundquist found that retroviruses like HIV bud from infected cells using the host Endosomal Sorting Pathway Required for Transport or ESCRT pathway. HIV also uses the host proteins of the Angiomotin family to facilitate membrane envelopment prior to ESCRT- mediated budding. Sundquist's current research in this area focuses on understanding assembly and budding of HIV, characterizing the host and viral proteins involved, and testing innate immune restriction of viruses that use the ESCRT pathway. The Sundquist lab has also used their understanding of the requirements and principles of enveloped virus assembly to design and characterize new proteins that can assemble into nanocages, bud from cells, and carry cargoes into new target cells.

• Garrus JE, von Schwedler UK, Pornillos O, Morham SG, Zavitz KH, Wang HE, Wettstein DA, Stray KM, Cöté M, Rich RL, Myszka DG, Sundquist WI. (2001). Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. Cell, 107, 55-65.

• von Schwedler U, Stuchell M, Müller B, Ward D, Chung H-Y, Morita E, Wang H, Davis T, Gong-Ping H, Cimbora DM, Scott AT, Kräusslich H-G, Kaplan J, Morham SG, and Sundquist WI. (2003). The protein network of HIV budding. Cell, 114, 701-713.

• Mercenne G, Alam SL, Arii J, Lalonde MS, Sundquist WI. (2015). Angiomotin functions in HIV-1 assembly and budding. eLife, 4, e03778.

• Votteler J, Ogohara C, Yi S, Hsia Y, Natterman U, Belnap DM, King NP, Sundquist WI. (2016). Designed proteins induce the formation of nanocage-containing extracellular vesicles. Nature, 540, 292-5

Asymmetric ring structure of Vps4 required for ESCRT III disassembly

The ESCRT pathway facilitates formation of vesicles that bud into the endosome, neuronal pruning, reassembly of the post-mitotic nuclear envelope and final stage cell division (cytokinetic abscission). Cytokinetic abscission completes the separation of the two daughter cells, and also helps to coordinate a checkpoint that delays cell division until mitotic processes are completed successfully. In some cancer cells, this pathway doesn’t function correctly. Sundquist’s lab is studying these processes by determining the structures and functions of individual ESCRT proteins and the cofactors they recruit to help mediate abscission and the abscission checkpoint, and the signaling pathways that control their activities.

• Scott A, Gaspar J, Stuchell-Brereton MD, Alam SL, Skalicky JJ, Sundquist WI. Structure and ESCRT-III protein interactions of the MIT domain of human VPS4A. (2005) PNAS, 102(39), 13813-13818.

• McCullough J, Clippinger AK, Talledge N, Skowyra ML, Saunders MG, Naismith TV, Colf LA, Afonine P, Arthur C, Sundquist WI, Hanson PI, Frost A. Structure and membrane remodeling activity of ESCRT-III helical polymers.(2015) Science, 350(6267), 1541-1551.

• Stuchell-Brereton MD, Skalicky JJ, Kieffer C, Karren MA, Ghaffarian S, Sundquist WI. ESCRT-III recognition by VPS4 ATPases. (2007) Nature, 449, 740-744.

• Morita E, Sandrin V, Chung HY, Morham SG, Gygi SP, Rodesch CK, Sundquist WI. (2007). Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesis. EMBO J, 26(19), 4215-27.

• 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.

HIV virion structure

The capsid of HIV facilitates viral reverse transcription and protects the viral genome from the innate immune system. Sundquist defined the fullerene cone structure of the viral capsid, helping to set the stage for development of highly potent and long-lasting capsid inibitors at Gilead Sciences. He and his colleagues also helped to define how the host restriction factor, TRIM5alpha recognizes and assembles around the capsid. The Sundquist lab is now investigating how the capsid promotes reverse transcription and other stages of viral replication.

• Ganser BK, Li S, Klishko VY, Finch JT, Sundquist WI. (1999). Assembly and analysis of conical models for the HIV-1 core. Science, 283(5398), 80-3.

• Li S, Hill CP, Sundquist WI, Finch JT. (2000). Image reconstructions of helical assemblies of the HIV-1 CA protein. Nature, 407(6802), 409-13.

• Pornillos O, Ganser-Pornillos BK, Kelly BN, Hua Y, Whitby FG, Stout CD, Sundquist WI, Hill CP, Yeager M. (2009). X-ray structures of the hexameric building block of the HIV capsid. Cell, 137(7), 1282-92.

• Li Y-L, 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.