Expression of OA1 limits the fusion of a subset of MVBs with lysosomes - a mechanism potentially involved in the initial biogenesis of melanosomes
Expression of OA1 limits the fusion of a subset of MVBs with lysosomes - a mechanism potentially involved in the initial biogenesis of melanosomes
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DOI：
10.1242/jcs.128561
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发表时间：
2013-11-15
影响因子：
4
通讯作者：
Futter, Clare E.
中科院分区：
文献类型：
--
作者：
Burgoyne, Thomas;Jolly, Rushee;Futter, Clare E.
多泡内体（MVBs）将蛋白质（如活化的EGF受体（EGFR））传递到溶酶体进行降解，并且在色素细胞中，含有PMEL的MVBs是黑素小体生物发生的初始阶段。调控不同种群MVB数量和命运的机制尚不清楚。在这里，我们关注的是g蛋白偶联受体OA1（也称为GPR143）的作用，它只在色素细胞和突变中表达，导致最常见的眼部白化病类型。当外源表达PMEL时，HeLa细胞已被证明形成类似早期黑素体的MVBs。为了研究OA1在黑素小体生物发生的初始阶段的作用，我们利用HeLa细胞中黑素小体成熟的后期缺失来确定OA1活性是否可以调节MVB的数量和命运。携带失活突变或缺失的野生型而非OA1突变体的表达会导致MVB数量增加。虽然OA1表达对含有egfr的MVBs向溶酶体的传递没有影响，但它抑制了PMEL的溶酶体传递和含有PMEL的MVBs的积累。我们认为OA1的活性延迟了含有pmel的MVBs向溶酶体的传递，从而为黑色素合成和黑色素小体的生物发生留出了时间。
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.