title: Expression of OA1 limits the fusion of a subset of MVBs with lysosomes - a mechanism potentially involved in the initial biogenesis of melanosomes.
abstract: Multivesicular endosomes/bodies (MVBs) deliver proteins, such as activated EGF receptor (EGFR), to the lysosome for degradation, and, in pigmented cells, MVBs containing PMEL are an initial stage in melanosome biogenesis. The mechanisms regulating numbers and fate of different populations of MVB are unclear. Here, we focus on the role of the G-protein-coupled receptor OA1 (also known as GPR143), which is expressed exclusively in pigmented cells and mutations in which cause the most common type of ocular albinism. When exogenously expressing PMEL, HeLa cells have been shown to form MVBs resembling early stage melanosomes. To focus on the role of OA1 in the initial stages of melanosome biogenesis we take advantage of the absence of the later stages of melanosome maturation in HeLa cells to determine whether OA1 activity can regulate MVB number and fate. Expression of wild-type but not OA1 mutants carrying inactivating mutations or deletions causes MVB numbers to increase. Whereas OA1 expression has no effect on delivery of EGFR-containing MVBs to the lysosome, it inhibits the lysosomal delivery of PMEL and PMEL-containing MVBs accumulate. We propose that OA1 activity delays delivery of PMEL-containing MVBs to the lysosome to allow time for melanin synthesis and commitment to melanosome biogenesis.
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Burgoyne
authors.forename: Rushee
authors.initials: R
authors.lastname: Jolly
authors.forename: Belen
authors.initials: B
authors.lastname: Martin-Martin
authors.forename: Miguel C
authors.initials: MC
authors.lastname: Seabra
authors.forename: Rosanna
authors.initials: R
authors.lastname: Piccirillo
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Schiaffino
authors.forename: Clare E
authors.initials: CE
authors.lastname: Futter
mesh_terms: D011992:Endosomes / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005136:Eye Proteins / Q000096:biosynthesis* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D020460:Melanosomes / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D057146:Multivesicular Bodies / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D058951:gp100 Melanoma Antigen / Q000378:metabolism
chemical_list: D005136:Eye Proteins; C095276:GPR143 protein, human; D008562:Membrane Glycoproteins; C548637:PMEL protein, human; D058951:gp100 Melanoma Antigen; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Lysosomes; Multivesicular bodies; OA1