Role of Drosophila Light in endo-lysosomal trafficking

Lysosomes are the primary degradative organelles of cells. In addition to
regulating protein turnover, lysosomes are also involved in several other
cellular processes such as modulation of signaling, antigen processing and
plasma membrane repair. In metazoans, these lysosomes are characterized by a
unique tubular morphology, acidic pH, and specific membrane protein (LAMP) and
lipid (cholesterol) composition as well as a soluble protein (hydrolases)
composition. Defects in lysosome formation and functioning have been long
associated with several lysosome storage disorders as well as some
multi-symptomatic syndromes such as Chediak Higashi syndrome and Hermansky
Pudlak syndromes. Thus, identifying and characterizing molecules that are
involved in lysosome biogenesis in a metazoan context is of importance.
In Drosophila, a subset of genes called the "Granule group" of eye color genes
affect the biogenesis of pigment granules, which are lysosome-related
organelles. Several of these genes, such as garnet, deep orange (dor) and
carnation, have also been shown to have a role in intracellular traffic. I
have examined the role of the eye color gene, light, in endo-lysosomal
trafficking. Perturbation of Light results in impaired lysosomal
acidification, sterol accumulation, altered lysosomal morphology as well as
compromised lysosomal degradation. I find that Drosophila Light regulates the
fusion of a specific subset of biosynthetic carriers containing characteristic
endolysosomal membrane proteins- LAMP1, V0-ATPase and the cholesterol
transport protein, NPC1, with the endo-lysosomal system, and is then required
for the morphological progression of the multivesicular endosome. Inhibition
of Light results in accumulation of biosynthetic transport intermediates that
contain these membrane cargo, whereas under similar conditions, endosomal
delivery of soluble hydrolases (previously shown to be mediated by Dor), is
not affected. Unlike Dor, Light is recruited to endosomes in a PI3P-sensitive
fashion wherein it facilitates fusion of these biosynthetic cargo with the
endosomes. Depletion of the mammalian counterpart of Light, hVps41, in a human
cell line also inhibits delivery of hLAMP to endosomes, suggesting an
evolutionarily conserved pathway in metazoa.