BBB Seminar: Graça Raposo-Benedetti
Endosome dynamics in the biogenesis of lysosome-related organelles
Structure and Membrane Compartments, National Center for Scientific Research (CNRS), Institut Curie, Paris, France
The endosomal system comprises a complex network of organelles and membrane subdomains with important functions in signal transduction, nutrient uptake, pathogen destruction and other essential processes. Our work on the melanosome, a lysosome-related organelle of pigment cells, has provided insight into mammalian endosomal membrane dynamics by revealing how specific trafficking events are exploited to generate tissue-specific organelles. Our recent studies have started to unravel how the endosomal system specializes to first generate unpigmented fibrillar melanosomes and then form the pigmented mature melanosomes that can be transfered to keratinocytes. During early melanogenesis, sorting of the protein Pmel17 to intraluminal vesicles of multivesicular body (MVB)-derived precursors of melanosomes occurs concomitantly with its cleavage and consequent formation of Pmel17-driven amyloid-like fibrils. Sorting of Pmel17 is independent of ubiquitination and the ESCRT (endosomal sorting complex required for transport) machinery. Further, our studies highlight a role for tetraspanins in endosomal sorting and the generation of amyloid-like fibrillar sheets in vitro and in vivo. Late melanogenesis requires the transfer of melanogenic enzymes from early endosomes to maturing melanosomes. Gene products mutated in different forms of albinism (such as the Hermansky-Pudlak syndrome) encode proteins that regulate late melanogenesis (AP-3, BLOC complexes). These novel traffic regulators operate in concert with additional adaptors, cytoskeletal motors and Rab GTPases to modulate endosomal sorting and positioning, thus facilitating the endosome-melanosome crosstalk required for biogenesis of functional organelles. The aim of our current work is to shed light on how specialized trafficking events can be regulated within the integrated epidermal-melanin unit upon establishment of the pigmentation synapse.
Host: Jaakko Saraste, Department of Biomedicine