Mechanisms and functions of lysosome positioning

Abstract

Lysosomes have been classically considered terminal degradative organelles, but in recent years they have been found to participate in many other cellular processes, including killing of intracellular pathogens, antigen presentation, plasma membrane repair, cell adhesion and migration, tumor invasion and metastasis, apoptotic cell death, metabolic signaling and gene regulation. In addition, lysosome dysfunction has been shown to underlie not only rare lysosome storage disorders but also more common diseases, such as cancer and neurodegeneration. The involvement of lysosomes in most of these processes is now known to depend on the ability of lysosomes to move throughout the cytoplasm. Here, we review recent findings on the mechanisms that mediate the motility and positioning of lysosomes, and the importance of lysosome dynamics for cell physiology and pathology.

Keywords: Dynein; Kinesin; Late endosome; Lysosome; Organelle motility; Organelle positioning.

Fig. 1.

Multiple functions of lysosomes are influenced by their positioning and motility. In addition to degradation, lysosomes participate in other cellular functions. Many of these functions, including endocytic, phagocytic and autophagic degradation, antigen presentation, killing of target cells by cytotoxic T-cells and NK cells, metabolic signaling, cell adhesion and migration, tumor invasion and metastasis, as well as plasma membrane repair, depend on the ability of lysosomes to move throughout the cytoplasm.

Fig. 2.

Distribution of lysosomes in HeLa cells. Wild-type (WT), myrlysin-knockout (KO), and SKIP-overexpressing HeLa cells were immunostained for the lysosomal membrane protein LAMP-1. In WT cells, lysosomes are scattered throughout the cytoplasm, although they have a greater concentration in the juxtanuclear area of the cells. In cells lacking the myrlysin subunit of BORC, lysosomes are more clustered in the juxtanuclear area and depleted from the periphery. In SKIP-overexpressing cells, lysosomes accumulate in the periphery. See Fig. 4 for a schematic representation of the roles of BORC and SKIP in lysosome positioning.

Fig. 3.

Kinesins implicated in lysosome movement. Family names, domains and amino acid numbers are indicated. CC, coiled coil; Gl, globular; FHA, forkhead-associated; UDR, undefined region; PH, pleckstrin-homology.

Fig. 4.

Mechanisms of late endosome and lysosome transport along microtubules. Anterograde transport of late endosome (LE) and lysosome transport is mediated by an ensemble of BORC, Arl8, SKIP and kinesin-1 (a heterotetramer composed of two KLC and two KIF5 chains). An alternative mechanism of anterograde transport uses Rab7 and FYCO1 as adaptors to kinesin-1. FYCO1 is loaded onto late endosomes by the action of the ER-anchored protrudin. Other kinesins depicted in Fig. 3 have also been shown to drive anterograde transport of lysosomes, but their mechanisms of coupling are less well understood. Retrograde transport is mediated by Rab7, RILP, ORP1L and dynein–dynactin. The names of some of the dynactin subunits are indicated (p150-glued, Arp1). Under low-cholesterol concentrations, ORP1L interacts with the ER-anchored protein VAPA, leading to dynein dissociation and redistribution of lysosomes to the cell periphery.

Fig. 5.

Lysosome movement in autophagy. Dynein-mediated retrograde transport of lysosomes promotes their fusion with autophagosomes to generate autolysosomes. This transport is sensitive to Ca²⁺ levels, which are sensed through TRPML1 and ALG-2. Autolysosomes also move in the retrograde direction through interaction with dynein. Kinesin-1 pulls tubular proto-lysosomes during autophagic lysosome reformation (ALR).

Fig. 6.

Lytic granule movement in cytotoxic T lymphocytes and natural killer cells. The scheme integrates findings from both cytotoxic T lymphocytes (CTLs) and natural killer (NK) types, although not all steps might be applicable to both cell types. The MTOC is relocated under the immune synapse. Dynein transports lytic granules from the cell center to the area underlying the immune synapse. Kinesin-1 then moves lytic granules closer to the plasma membrane, where myosin IIa attaches them to actin filaments, and Rab27a and Munc13-4 promote their fusion with the plasma membrane. TCR, T-cell receptor.