Lukas Tamm, School of Medicine, University of Virginia

Host: Susan Daniel & Gerald Feigenson

Multiple roles of cholesterol in cell entry of HIV and Ebola viruses and exocytotic fusion pore formation

Cholesterol plays complex roles in modulating the dynamical structure of cell membranes. For example, viral envelope proteins such as influenza HA, HIV gp120/gp41, and Ebola GP1/GP2 utilize cholesterol-rich lipid domains to bud off cell membranes and to enter cells by membrane fusion. Interestingly, we found recently that the perimeters and not the platforms of cholesterol-rich lipid domains (“rafts”) constitute the main sites of HIV entry by membrane fusion. These viruses take advantage of “line tension” that exists at raft boundaries for cell entry. Similarly, membrane-integral SNARE proteins that are responsible for rapid membrane fusion in synaptic exocytosis redistribute in the membranes in a fashion that is tightly regulated by cholesterol and the signaling lipid PIP2.  Single particle fusion assays show that the progression of an initial hemi-fusion intermediate to an open exocytotic fusion pore is strongly promoted by cholesterol.

References:

• Yang ST, Kreutzberger AJ, Lee J, Kiessling V, (2016) The role of cholesterol in membrane fusion. Chem Phys Lipids 199:136-143.
• Kreutzberger AJB, Kiessling V, and Tamm LK (2015) High cholesterol obviates a prolonged hemifusion intermediate in fast SNARE-mediated membrane fusion. Biophys J 109:1-11.
• Simmons JA, White JM, and Tamm LK (2015) HIV gp41-mediated membrane fusion occurs at edges of cholesterol-rich lipid domains. Nature Chem Biol 11:424-431.
• Yang ST, Kiessling V, Tamm LK (2016) Line tension at lipid phase boundaries as a driving force for HIV fusion peptide-mediated fusion. Nat Commun 7:11401.

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