Cell biology and biochemistry of protein transport towards lysosome-related organelles

早期内体是一个重要的分选站，用于再循环到质膜或高尔基体网络的货物蛋白，以及用于注定要进入溶酶体的蛋白质。结合管腔货物的跨膜货物蛋白或分选受体在其胞质结构域内具有分选信号。因此，细胞内稳态的维持需要一个系统，该系统识别货物蛋白上的这些决定因素，并将它们引导到注定用于特定靶细胞器的出芽囊泡。运输货物到溶酶体的缺陷导致异常的溶酶体功能并导致溶酶体贮积病。除了在广泛底物降解中起作用的正常溶酶体之外，某些细胞类型含有专门的溶酶体，称为溶酶体相关细胞器（LRO），其实现生物合成和储存功能。LRO的一个突出例子是黑素细胞中的黑素体，其合成并储存色素黑色素。我们特别感兴趣的是一组蛋白质复合物，称为生物合成的溶酶体相关的细胞器复合物（BLOC），参与蛋白质运输到LRO。Hermansky-Pudlak综合征（HPS）是一组BLOC复合物缺陷导致白化病、长期出血、肺纤维化和溃疡性结肠炎的疾病。有三个BLOC，分别命名为BLOC-1、BLOC-2和BLOC-3。BLOC-1复合物在LRO生物发生的早期阶段需要运输LRO的关键组分，但其在该过程中的确切作用尚未得到解决。我们的目标是使用细胞生物学，生物化学和结构的方法来了解BLOC-1在分子水平上的功能。一个主要的目标是确定BLOC-1复合物的调节因子和效应因子，以便将BLOC-1功能整合到负责黑素体生物发生的细胞机制中。

The early endosome is a an important sorting station for cargo proteins that recycle to the plasma membrane or the trans-Golgi-network, as well as for proteins destined to the lysosome. Transmembrane cargo proteins or sorting receptors that bind luminal cargo have sorting signals within their cytosolic domains. Maintenance of cellular homeostasis thus requires a system that recognizes these determinants on cargo proteins and directs them to budding vesicles destined for a specific target organelle. Defects in transport of cargo to lysosomes leads to aberrant lysosome function and results in lysosomal storage diseases. In addition to normal lysosomes, which function in the degradation of a broad range of substrates, certain cell types contain specialized lysosomes, termed lysosome-related organelles (LROs), that fulfill biosynthetic and storage functions. A prominent example for LROs are melanosomes in melanocytes that synthesize and store the pigment, melanin. We are particularly interested in a group of protein complexes termed biogenesis of lysosome-related organelle complexes (BLOC) that are involved in protein trafficking to LROs. Hermansky-Pudlak Syndrome (HPS) is a group of disorders in which defects in BLOC complexes cause albinism, prolonged bleeding, pulmonary fibrosis and ulcerative colitis. There are three BLOCs named BLOC-1, BLOC-2 and BLOC-3. The BLOC-1 complex is required to transport critical components of LROs at an early stage of their biogenesis, yet its precise role in the process has not been resolved. We aim to use cell biological, biochemical and structural methods to understand BLOC-1 function at the molecular level. A major goal is to identify regulators and effectors of the BLOC-1 complex in order to integrate BLOC-1 function into a cellular machinery responsible for melanosome biogenesis.