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

早期的内体是回收到质膜或跨高尔基网络的货物蛋白质以及运往溶酶体的蛋白质的重要分拣站。结合管腔货物的跨膜货物蛋白或分选受体在其胞质区域内具有分选信号。因此，维持细胞的动态平衡需要一个系统来识别货物蛋白上的这些决定因素，并将它们引导到去往特定目标细胞器的萌芽小泡。货物运输到溶酶体的缺陷会导致溶酶体功能异常，并导致溶酶体储存性疾病。除了正常的溶酶体外，某些细胞类型还含有特殊的溶酶体，称为溶酶体相关细胞器(LRO)，完成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小体，它合成和存储黑色素。我们特别感兴趣的是一组蛋白质复合体，称为溶酶体相关细胞器复合体的生物发生(BLOC)，它们参与蛋白质向LRO的运输。Hermansky-Pudlak综合征(HPS)是一组疾病，其中块复合体缺陷会导致白化、出血延长、肺纤维化和溃疡性结肠炎。有三个区块，分别命名为区块1、区块2和区块3。在LRO生物发生的早期阶段，BLOC-1复合体需要运输LRO的关键成分，但它在这一过程中的确切作用尚未确定。我们的目标是使用细胞生物学、生化和结构方法在分子水平上了解BLOC-1的功能。一个主要的目标是确定BLOC-1复合体的调节因子和效应器，以便将BLOC-1的功能整合到负责黑素小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.