PIKfyve complex regulates early melanosome homeostasis required for physiological amyloid formation
Year: 2019
Type: article
Abstract: The metabolism of PI(3,5)P2 is regulated by the PIKfyve, VAC14 and FIG4 complex, mutations in which are associated with hypopigmentation in mice. These pigmentation defects indicate a key, but as yet unexplored, physiological relevance of this complex in the biogenesis of melanosomes. Here, we show that PIKfyve activity regulates formation of amyloid matrix composed of PMEL protein within the early endosomes in melanocytes, called stage I melanosomes. PIKfyve activity controls the membrane remodeling of stage I melanosomes, which regulates PMEL abundance, sorting and processing. PIKfyve activity also affects stage I melanosome kiss-and-run interactions with lysosomes, which are required for PMEL amyloidogenesis and the establishment of melanosome identity. Mechanistically, PIKfyve activity promotes both the formation of membrane tubules from stage I melanosomes and their release by modulating endosomal actin branching. Taken together, our data indicate that PIKfyve activity is a key regulator of the melanosomal import-export machinery that fine tunes the formation of functional amyloid fibrils in melanosomes and the maintenance of melanosome identity.This article has an associated First Person interview with the first author of the paper.
Source: Journal of Cell Science
DOI: 10.1242/jcs.229500
Institutions: Centre National de la Recherche Scientifique, Université Paris Sciences et Lettres, Biologie cellulaire et Cancer, Institut Curie, Inserm, Institut de Psychiatrie et Neurosciences de Paris, Centre for Psychiatry and Neuroscience, Université Paris Descartes, University of Michigan, VIB-KU Leuven Center for Brain & Disease Research, KU Leuven
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: bronze
Funders: Amyloidosis Foundation, Hercules Foundation, Federation of European Biochemical Societies, Infrastructures en Biologie Santé et Agronomie, Agence Nationale de la Recherche, Fondation pour la Recherche Médicale, Fonds Wetenschappelijk Onderzoek, KU Leuven, Fondation ARC pour la Recherche sur le Cancer, Vlaams Instituut voor Biotechnologie, Centre National de la Recherche Scientifique, Institut Curie, Labex CelTisPhyBio, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: Roles and regulation of PI(3,5)P2 and PI5P in neurons, G120131529, Bridging microscopy with nanotechnology and interactomics to probe the membrane microenvironment of distinct y-secretase complexes in cells and neurons and to identify complex-specific interactors, G1312232433, Integrated platform to validate vesicular trafficking-associated processes in neurodegenerative diseases., Paris Sciences et Lettres, G3089088799, G3489752117, G3795266850, G4190806336, G471331628, G4863663589, G506201278, G5148354177, G5610283560, G5725192546, G5835340202, G6358499467, G6682653184, G6759105742, G7148274955, G7197993365, G7240651115, G782245399, G9000064584, G9000076199, G903127411, G940301113
OpenAlex ID: W2914134017