Molecular and Mechanistic Studies of Membrane Stabilization and Repair
The endolysosomal network is the portal by which extracellular material enters the cell. As such, membranes of the endosomes, phagosomes, and lysosomes that comprise this network undergo dramatic remodeling as they sort and metabolize internalized material. Importantly, these membranes are vulnerable to damage and permeabilization by metabolic and chemical stresses as well as pathogens and particulate debris. Consequences of damage vary depending on the specific compartment and cell type, leading to responses such as lipid remodeling, inflammation, infection, and cell death.
We address key questions about membrane repair using biochemical, cellular, and imaging approaches:
1) What are early signals of stress and nanoscale damage to organelle membranes? Do these differ for organelles and for the plasma membrane?
2) How are specific ESCRTs recruited to damaged membranes?
3) How do ESCRTs stabilize and/or repair membranes?
4) How do ESCRTs cooperate with other machinery involved in membrane repair?
5) How are irreparable organelles triaged for removal?
Organelle membrane damage and repair is a rapidly developing area of research with the potential to seed new therapeutic approaches to a wide range of infectious, inflammatory, and degenerative diseases along with implications for bioengineering endosomal escape.
ESCRT Machinery in Endosomal Trafficking
ESCRT proteins carry out a wide variety of functions within the cell. On endosomes, ESCRTs create intralumenal vesicles but also contribute to membrane recycling. Twelve human ESCRT-III proteins and the AAA+ ATPases VPS4A and VPS4B make all of this possible, working to drive membrane scission. We are interested in understanding how these proteins operate, how selectivity for different processes is controlled, and how their dysfunction contributes to disease pathogenesis.
Images
Autoinhibitory linker connecting MIT and AAA+ domain in VPS4A
ESCRT-III on LLOME-disrupted lysosomes
Loss of ESCRTs impairs recovery from transient lysosomal disruption