Biogenesis and Functions of Lysosome-Related Organelles

Raposo Graça

Graça Raposo Chef d'équipe Tel:

The organelles of the endocytic pathway serve many ‘housekeeping’ functions such as taking up nutrients, controlling signaling pathways and degrading unwanted macromolecules. In addition, these organelles are involved in a diverse range of more specific cellular functions.

The major goals of our research are to gain a better understanding of the biogenesis and functions of two such specialized endosomal organelles: exosomes, which are secreted from multivesicular bodies, and the lysosome-related organelles called melanosomes which synthesize the pigment melanin.

Figure 1: Functional modulations of the endocytic pathway: Melanosomes and Exosomes. Melanosomes originate from the endocytic pathway but remain distinct from lysosomes. PMEL, is transported to Stage II premelanosomes via early endosomes (EE) and Stage I premelanosomes.Tyrosinase and TYRP1 traffic through recycling endosomes to be targeted to the maturing melanosome. Fusion of MVBs with the plasma membrane and exosome secretion is also represented. Adapted from Delevoye et al., Med.Sciences, 2011 and Raposo and Stoorvogel, JCB 2013
Figure 1: Functional modulations of the endocytic pathway: Melanosomes and Exosomes. Melanosomes originate from the endocytic pathway but remain distinct from lysosomes. PMEL, is transported to Stage II premelanosomes via early endosomes (EE) and Stage I premelanosomes.Tyrosinase and TYRP1 traffic through recycling endosomes to be targeted to the maturing melanosome. Fusion of MVBs with the plasma membrane and exosome secretion is also represented. Adapted from Delevoye et al., Med.Sciences, 2011 and Raposo and Stoorvogel, JCB 2013

 

Figure 2: Melanosome maturation requires a close dialogue with specialized Recycling Endosomes Left panel: electron tomography of the endosomal-melanosomal system (endosomes in green, melanosomes in red). Right panel: Representative model of the molecular mechanisms involved in protein sorting and endosome positioning in melanocytes. Delevoye et al., J Cell Biology 2009; Delevoye et al. Cell Rep. 2014.siRNAs and small peptides were developed to inhibit these molecular interactions, which open a path to modulate skin pigmentation in pigmentary disorders.
Figure 2: Melanosome maturation requires a close dialogue with specialized Recycling Endosomes Left panel: electron tomography of the endosomal-melanosomal system (endosomes in green, melanosomes in red). Right panel: Representative model of the molecular mechanisms involved in protein sorting and endosome positioning in melanocytes. Delevoye et al., J Cell Biology 2009; Delevoye et al. Cell Rep. 2014.siRNAs and small peptides were developed to inhibit these molecular interactions, which open a path to modulate skin pigmentation in pigmentary disorders.

Our studies are carried out using a variety of human and mouse cell types in culture by combining electron microscopy with light microscopy, biochemistry and siRNA. Melanosomes are cell type-specific membrane-bound organelles within ocular pigment epithelial cells and ocular and epidermal melanocytes in which melanin pigments are synthesized and stored.  They are considered “lysosome-related organelles” that have unique morphological and functional features. Among lysosome-related organelles, melanosomes are part of a subclass that coexists with bona fide late endosomes and lysosomes.  Over the past years we have addressed the cellular and molecular mechanisms regulating the formation of melanosomes in epidermal melanocytes. Through a fruitful combination of light and electron microscopy, molecular biology and biochemistry, our studies have provided a conceptual framework to decipher novel trafficking pathways that underlie melanosome formation and to understand how different cellular machineries cooperate to control these pathways. Our studies have shed light on the complexity of the endosomal system of melanocytes, the pathogenesis of Hermansky-Pudlak Syndrome (HPS) and related disorders of lysosome-related organelles, the formation of amyloid fibrils in neurodegenerative diseases, and alterations of intracellular trafficking that occur during progression to melanoma. We anticipate that new insights will contribute to the development of novel therapeutic strategies for pigment and neurodegenerative diseases and melanoma.

Key publications

Year of publication 2014

Guillaume van Niel, Ptissam Bergam, Aurelie Di Cicco, Ilse Hurbain, Alessandra Lo Cicero, Florent Dingli, Roberta Palmulli, Cecile Fort, Marie Claude Potier, Leon J Schurgers, Damarys Loew, Daniel Levy, Graça Raposo (2014 Nov 13)

Apolipoprotein E Regulates Amyloid Formation within Endosomes of Pigment Cells.

Cell reports : 43-51 : DOI : 10.1016/j.celrep.2015.08.057
Mathieu Boissan, Guillaume Montagnac, Qinfang Shen, Lorena Griparic, Jérôme Guitton, Maryse Romao, Nathalie Sauvonnet, Thibault Lagache, Ioan Lascu, Graça Raposo, Céline Desbourdes, Uwe Schlattner, Marie-Lise Lacombe, Simona Polo, Alexander M van der Bliek, Aurélien Roux, Philippe Chavrier (2014 Jun 28)

Membrane trafficking. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling.

Science (New York, N.Y.) : 1510-5 : DOI : 10.1126/science.1253768
Carine Rossé, Catalina Lodillinsky, Laetitia Fuhrmann, Maya Nourieh, Pedro Monteiro, Marie Irondelle, Emilie Lagoutte, Sophie Vacher, François Waharte, Perrine Paul-Gilloteaux, Maryse Romao, Lucie Sengmanivong, Mark Linch, Johan van Lint, Graça Raposo, Anne Vincent-Salomon, Ivan Bièche, Peter J Parker, Philippe Chavrier (2014 Apr 21)

Control of MT1-MMP transport by atypical PKC during breast-cancer progression.

Proceedings of the National Academy of Sciences of the United States of America : E1872-9 : DOI : 10.1073/pnas.1400749111

Year of publication 2013

Xavier Heiligenstein, Jérôme Heiligenstein, Cédric Delevoye, Ilse Hurbain, Sabine Bardin, Perrine Paul-Gilloteaux, Lucie Sengmanivong, Gilles Régnier, Jean Salamero, Claude Antony, Graca Raposo (2013 Aug 28)

The CryoCapsule: simplifying correlative light to electron microscopy.

Traffic (Copenhagen, Denmark) : 700-16 : DOI : 10.1111/tra.12164
Leila Rochin, Ilse Hurbain, Lutgarde Serneels, Cecile Fort, Brenda Watt, Pascal Leblanc, Michael S Marks, Bart De Strooper, Graça Raposo, Guillaume van Niel (2013 Jun 10)

BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells.

Proceedings of the National Academy of Sciences of the United States of America : 10658-63 : DOI : 10.1073/pnas.1220748110
Graça Raposo, Willem Stoorvogel (2013 Feb 20)

Extracellular vesicles: exosomes, microvesicles, and friends.

The Journal of cell biology : 373-83 : DOI : 10.1083/jcb.201211138
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