Functional redundancy of Rab27 proteins and the pathogenesis of Griscelli syndrome
Functional redundancy of Rab27 proteins and the pathogenesis of Griscelli syndrome
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DOI：
10.1172/jci200215058
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发表时间：
2002-07-01
影响因子：
15.9
通讯作者：
Seabra, MC
中科院分区：
文献类型：
--
作者：
Barral, DC;Ramalho, JS;Seabra, MC
格里斯利综合征（GS）患者和相应的灰白小鼠模型主要表现出两类溶酶体相关细胞器的缺陷，即黑素细胞中的黑素体和CTL中的抒情颗粒。这种疾病是由 RAB27A 的功能缺失突变引起的，RAB27A 编码 60 种已知 Rab GTP 酶中的 I，这是囊泡运输的关键调节因子。在这里，我们提供的证据表明 Rab27a 功能可以通过密切相关的蛋白质 Rab27b 来补偿。 Rab27b 在血小板和其他组织中表达，但在黑素细胞或 CTL 中不表达。来自 ashen 小鼠的血小板的形态学和功能测试均在正常范围内。发现 Rab27a 和 Rab27b 均与血小板致密颗粒的界限膜相关，并在较小程度上与 α 颗粒相关。 Rab27a 或 Rab27b 的普遍转基因表达挽救了灰白色的皮毛颜色，来自转基因小鼠的黑素细胞表现出广泛的黑素体外周分布，而不是在灰白色黑素细胞中观察到的核周聚集。最后，Rab27a 或 Rab27b（而非其他 Rab）在灰黑色素细胞中的瞬时表达恢复了黑素体的外周分布。我们的数据表明，Rab27b 在功能上与 Rab27a 冗余，并且 GS 的发病机制是由特定细胞类型中 Rab27a 和 Rab27b 的相对表达决定的。
Griscelli syndrome (GS) patients and the corresponding mouse model ashen exhibit defects mainly in two types of lysosome-related organelles, melanosomes in melanocytes and lyric granules in CTLs. This disease is caused by loss-of-function mutations in RAB27A, which encodes I of the 60 known Rab GTPases, critical regulators of vesicular transport. Here we present evidence that Rab27a function can be compensated by a closely related protein, Rab27b. Rab27b is expressed in platelets and other tissues but not in melanocytes or CTLs. Morphological and functional tests in platelets derived from ashen mice are all within normal limits. Both Rab27a and Rab27b are found associated with the limiting membrane of platelet-dense granules and to a lesser degree with alpha-granules. Ubiquitous transgenic expression of Rab27a or Rab27b rescues ashen coat color, and melanocytes derived from transgenic mice exhibit widespread peripheral distribution of melanosomes instead of the perinuclear clumping observed in ashen melanocytes. Finally, transient expression in ashen melanocytes of Rab27a or Rab27b, but not other Rab's, restores peripheral distribution of melanosomes. Our data suggest that Rab27b is functionally redundant with Rab27a and that the pathogenesis of GS is determined by the relative expression of Rab27a and Rab27b in specialized cell types.