Professor Paul Luzio

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.