Biology subjects

Sviderskaya, E. V.

Publications and source records attributed to Sviderskaya, E. V..

3 recordsLinked to original sources

bioRxiv2024

Enhanced MC1R-signalling and pH modulation facilitate melanogenesis within late endosomes of BLOC-1-deficient melanocytes

Photoprotective melanins in the skin are synthesised by epidermal melanocytes within specialised lysosome-related organelles called melanosomes. Melanosomes coexist with lysosomes; thus, melanocytes employ specific trafficking machineries to ensure correct cargo delivery to either the endolysosomal system or maturing melanosomes. Mutations in some of the protein complexes required for melanogenic cargo delivery, such as biogenesis of lysosome-related organelles complex 1 (BLOC-1), result in hypopigmentation due to mistrafficking of cargo to endolysosomes. We show that hypopigmented BLOC-1-deficient melanocytes retain melanogenic capacity that can be enhanced by treatment with cAMP elevating agents despite the mislocalisation of melanogenic proteins. The melanin formed in BLOC-1-deficient melanocytes is not generated in melanosomes but rather within late endosomes/lysosomes to which some cargoes mislocalise. Although these organelles generally are acidic, a cohort of late endosomes/lysosomes have a sufficiently neutral pH to facilitate melanogenesis, perhaps due to mislocalised melanosomal transporters and melanogenic enzymes. Modulation of the pH of late endosomes/lysosomes by genetic manipulation or via treatment with lysosomotropic agents significantly enhances the melanin content of BLOC-1-deficient melanocytes. Our data suggest that upregulation of mistargeted cargoes can facilitate reprogramming of a subset of endolysosomes to generate some functions of lysosome-related organelles.

cell biology↗

bioRxiv2020

SLC45A2 protein stability and regulation of melanosome pH determine melanocyte pigmentation

SLC45A2 encodes a putative transporter expressed primarily in pigment cells. SLC45A2 mutations and polymorphisms cause oculocutaneous albinism (OCA) and pigmentation variation, but neither SLC45A2 localization and function nor how gene variants affect these properties are known. We show that SLC45A2 localizes to mature melanosomes that only partially overlap with a cohort expressing the chloride channel OCA2. SLC45A2 expressed ectopically in HeLa cells localizes to lysosomes and raises lysosomal pH, suggesting that, like OCA2, SLC45A2 in melanocytes de-acidifies maturing melanosomes to support melanin synthesis. Analyses of SLC45A2- and OCA2-deficient mouse melanocytes show that SLC45A2 functions later during melanosome maturation than OCA2, and that OCA2 overexpression compensates for loss of SLC45A2 expression in pigmentation. The light skin-associated SLC45A2 allelic F374 variant restores only moderate pigmentation to SLC45A2-deficient melanocytes because of low level expression in melanosomes due to rapid proteasome-independent degradation. Our data indicate that SLC45A2 maintains melanosome neutralization - initially orchestrated by transient OCA2 activity - to support melanization at late stages of melanosome maturation, and that a common variant imparts reduced activity due to protein instability.

cell biology↗

bioRxiv2018

Rab27a co-ordinates actin-dependent transport by controlling organelle-associated motors and track assembly proteins.

Cell biologists generally consider that microtubules and actin play complementary roles in long- and short-distance transport in animal cells. On the contrary, using melanosomes of melanocytes as a model, we recently discovered that motor myosin-Va, works with dynamic actin tracks, to drive long-range organelle dispersion in microtubule depleted cells. This suggests that in animals, as in yeast and plants, myosin/actin can drive long-range transport. Here we show that SPIRE1/2 and formin-1 (FMN1) proteins generate actin tracks required for myosin-Va-dependent transport in melanocytes. Moreover we show that, in addition to melanophilin/myosin-Va, Rab27a can recruit SPIRE1/2 to melanosomes, thereby integrating motor and track assembly activity at the organelle membrane. Based on this we suggest a model in which organelles and force generators (motors and track assemblers) are linked forming a cell-wide network that allows their collective activity to rapidly disperse the population of organelles long-distance throughout the cytoplasm.

cell biology↗