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Cambridge Institute for Medical Research


Membrane traffic in the late endocytic pathway

General audience summary:
Cells are compartmentalized by specialized organelles (little organs within each cell), and cargo including proteins is moved between these compartments by trafficking of vesicles. We aim to understand how the membrane traffic machinery moves specific proteins around the cell for their normal function and for their degradation, the latter taking place in the lysosome organelle. We hope our work will contribute to: the understanding of many diseases, including diabetes, atherosclerosis and neurodegenerative diseases, where defects in the cell surface and/or in membrane traffic occur; and infectious diseases where microbes subvert the membrane traffic system in order to infect cells. It will also contribute to developing better ways of targeting drugs to particular sites within cells for more specific drug therapies.

Strategic CIMR Themes: Membrane Trafficking, Organelle Biology

Funding: Medical Research Council, BBSRC

Research Group members: Nicholas Bright,  Iona Saval; joint with Prof. DJ Owen: Luther Davis, Sally Gray, Veronica Kane Dickson


Membrane traffic in the late endocytic pathway

Delivery of endocytosed macromolecules to endolysosomes and the regeneration of lysosomes are essential for cellular health, metabolism as well as both susceptibility and resistance to infection.  In mammalian cells, lysosomes are small membrane bound organelles ~0.5µm diameter, which are full of proteases and other hydrolytic enzymes and have long been regarded as the terminal compartment of the endocytic, phagocytic and autophagic pathways. We have found that the terminal compartment of the endocytic pathway is made up of acidic endolysosomes in which acid hydrolases, including cathepsins B, C and L, are catalytically active and acid hydrolase-inactive, neutral, terminal storage lysosomes. The latter kiss and fuse with late endosomes (also known as multivesicular bodies) to form endolysosomes.  Live cell microscopy experiments have shown that activation of the acid hydrolases always occurs after kissing commences, with a time lag of ~2-4 min. Endolysosomes digest endocytosed macromolecules, can signal to the nucleus and are transient intracellular compartments from which storage lysosomes are reformed. We study the membrane traffic machinery of the late endocytic pathway, including the role of the ESCRT (endosomal sorting complex required for transport), HOPS ((homotypic fusion and vacuole protein sorting) and SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complexes, as well as ion channels and the multifunctional protein VARP (Vps9 and ankyrin repeat containing protein), which regulates the function of the SNARE protein, VAMP7. We aim to understand the coordination of fusion and fission events in the lysosome regeneration cycle linking endolysosomes and terminal storage lysosomes as well as the disruption of this cycle that occurs in some diseases. We collaborate with David Owen to integrate the structural and cell biology of the membrane traffic machinery functioning in the late endocytic pathway.


Key publications: 

Bright NA*, Davis LJ & Luzio JP.* Endolysosomes are the principal intracellular sites of acid hydrolase activity. Curr. Biol. 26, 2233-2245 (2016).* equal corresponding authors.

Wartosch L*, Günesdogan U, Graham SC & Luzio JP.* Recruitment of VPS33A to HOPS by VPS16 is required for lysosome fusion with endosomes and autophagosomes.  Traffic doi:10.1111/tra.12283 *equal corresponding authors (2015).

Hesketh GG, Pérez-Dorado I, Jackson LP, Wartosch L, Schäfer IB, Gray SR, McCoy AJ, Zeldin OB, Garman EF, Harbour ME, Evans PR, Seaman MNJ*, Luzio JP * & Owen DJ.* VARP is recruited on to endosomes by direct interaction with retromer, where together they function in export to the cell surface. Dev. Cell 29, 591-606 *equal last authors (2014). 

Luzio JP, Hackmann Y, Dieckmann NMG & Griffiths GM. The Biogenesis of Lysosomes and Lysosome-Related Organelles. Cold Spring Harbor Perspect. Biol. 6, a016840 (2014).

Graham SC*, Wartosch L, Gray SR, Scourfield EJ, Deane JE, Luzio JP* & Owen DJ.  Structural basis of Vps33A recruitment to the human HOPS complex by Vps16. Proc. Natl Acad. Sci. USA 110, 13345–13350 *equal corresponding authors (2013).

Schäfer IB, Hesketh GG, Bright NA, Gray SR, Pryor PR, Evans PR, Luzio JP* & Owen DJ. * The binding of Varp to VAMP7 traps VAMP7 in a closed, fusogenically inactive conformation.  Nature Struct. Mol. Biol. 19, 1300–1309  *equal last authors (2012).

Emeritus Professor of Molecular Membrane Biology

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Departments and institutes: 
St Edmund's College