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SLC45A2 protein stability and regulation of melanosome pH determine melanocyte pigmentation
- Source :
- Molecular Biology of the Cell
- Publication Year :
- 2020
- Publisher :
- American Society for Cell Biology (ASCB), 2020.
-
Abstract
- SLC45A2 encodes a putative transporter expressed primarily in pigment cells. SLC45A2 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.
- Subjects :
- Male
SLC45A2
genetic structures
Skin Pigmentation
Melanocyte
Cell Line
Mice
03 medical and health sciences
Melanin synthesis
0302 clinical medicine
Protein stability
Antigens, Neoplasm
Chloride Channels
medicine
Animals
Humans
Molecular Biology
Skin
030304 developmental biology
Melanosome
0303 health sciences
Melanosomes
biology
Pigmentation
Protein Stability
Membrane Transport Proteins
Pigment cells
Transporter
Articles
Cell Biology
medicine.disease
Oculocutaneous albinism
Cell biology
medicine.anatomical_structure
Cell Biology of Disease
030220 oncology & carcinogenesis
biology.protein
Melanocytes
Carrier Proteins
Lysosomes
HeLa Cells
Subjects
Details
- ISSN :
- 19394586 and 10591524
- Volume :
- 31
- Database :
- OpenAIRE
- Journal :
- Molecular Biology of the Cell
- Accession number :
- edsair.doi.dedup.....2a0cae089f8c3c71a2747668a8d619ad