SLC45A2 protein stability and regulation of melanosome pH determine melanocyte pigmentation
encodes a putative transporter expressed primarily in pigment cells. mutations cause oculocutaneous albinism type 4 (OCA4) and polymorphisms are associated with pigmentation variation, but the localization, function, and regulation of SLC45A2 and its variants remain unknown. We show that SLC45A2 loc...
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| Published in: | Molecular biology of the cell Vol. 31; no. 24; pp. 2687 - 2702 |
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| Main Authors: | , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
The American Society for Cell Biology
15-11-2020
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| Online Access: | Get full text |
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| Summary: | encodes a putative transporter expressed primarily in pigment cells.
mutations cause oculocutaneous albinism type 4 (OCA4) and polymorphisms are associated with pigmentation variation, but the localization, function, and regulation of SLC45A2 and its variants remain unknown. We show that SLC45A2 localizes to a cohort of mature melanosomes that only partially overlaps with the cohort expressing the chloride channel OCA2. SLC45A2 expressed ectopically in HeLa cells localizes to lysosomes and raises lysosomal pH, suggesting that in melanocytes SLC45A2 expression, like OCA2 expression, results in the deacidification of maturing melanosomes to support melanin synthesis. Interestingly, OCA2 overexpression compensates for loss of SLC45A2 expression in pigmentation. Analyses of SLC45A2- and OCA2-deficient mouse melanocytes show that SLC45A2 likely functions later during melanosome maturation than OCA2. Moreover, the light skin-associated SLC45A2 allelic F374 variant restores only moderate pigmentation to SLC45A2-deficient melanocytes due to rapid proteasome-dependent degradation resulting in lower protein expression levels in melanosomes than the dark skin-associated allelic L374 variant. Our data suggest that SLC45A2 maintains melanosome neutralization that is initially orchestrated by transient OCA2 activity to support melanization at late stages of melanosome maturation, and that a common allelic variant imparts reduced activity due to protein instability. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conflict of interest: The authors of this manuscript have no conflicts of interest to declare. These authors contributed equally to this work. Author contributions: L.L. designed and performed most of the experiments shown in the paper, designed and performed all of the statistical analyses, assembled all of the figures, and participated in drafting and editing the manuscript; I.E.E. performed some of the experiments shown in the paper and repeated others, assembled drafts of the figures for these experiments, and edited the manuscript; T.H. and A.J.L. designed and performed some of the experiments shown in the paper, as well as experiments that formed the basis for other figures in the paper and that contributed to the quantification and statistical analyses of data shown, and both edited the manuscript; E.L., M.K.D., and K.D.H. designed and performed experiments that formed the basis of the project and that were included in the quantification and statistical analyses of data shown, and edited the manuscript; E.V.S. and D.C.B. developed the immortalized melan-uw melanocyte cell lines and edited the manuscript; E.O. and M.S.M. conceived the project, contributed to the design of most of the experiments, assembled figures, and participated in drafting and editing the manuscript. |
| ISSN: | 1059-1524 1939-4586 |
| DOI: | 10.1091/mbc.e20-03-0200 |