PDF(Pubmed)
Abstract：
The Hermansky Pudlak syndromes (HPS) constitute a family of disorders characterized by oculocutaneous albinism and bleeding diathesis, often associated with lethal lung fibrosis. HPS results from mutations in genes of membrane trafficking complexes that facilitate delivery of cargo to lysosome-related organelles. Among the affected lysosome-related organelles are lamellar bodies (LB) within alveolar type 2 cells (AT2) in which surfactant components are assembled, modified, and stored. AT2 from HPS patients and mouse models of HPS exhibit enlarged LB with increased phospholipid content, but the mechanism underlying these defects is unknown. We now show that AT2 in the pearl mouse model of HPS type 2 lacking the adaptor protein 3 complex (AP-3) fails to accumulate the soluble enzyme peroxiredoxin 6 (PRDX6) in LB. This defect reflects impaired AP-3-dependent trafficking of PRDX6 to LB, because pearl mouse AT2 cells harbor a normal total PRDX6 content. AP-3-dependent targeting of PRDX6 to LB requires the transmembrane protein LIMP-2/SCARB2, a known AP-3-dependent cargo protein that functions as a carrier for lysosomal proteins in other cell types. Depletion of LB PRDX6 in AP-3- or LIMP-2/SCARB2-deficient mice correlates with phospholipid accumulation in lamellar bodies and with defective intraluminal degradation of LB disaturated phosphatidylcholine. Furthermore, AP-3-dependent LB targeting is facilitated by protein/protein interaction between LIMP-2/SCARB2 and PRDX6 in vitro and in vivo Our data provide the first evidence for an AP-3-dependent cargo protein required for the maturation of LB in AT2 and suggest that the loss of PRDX6 activity contributes to the pathogenic changes in LB phospholipid homeostasis found HPS2 patients.
摘要：
HermanskyPudlak综合征（HPS）构成了一系列以眼皮肤白化病和出血素质为特征的疾病，常伴有致命性肺纤维化.HPS起因于膜运输复合物的基因中的突变,其促进货物递送至溶酶体相关的细胞器。受影响的溶酶体相关细胞器是肺泡2型细胞（AT2）中的层状体（LB），其中表面活性剂成分被组装，已修改,并存储。来自HPS患者和HPS小鼠模型的AT2表现出增大的LB，磷脂含量增加，但这些缺陷背后的机制尚不清楚。我们现在表明，缺乏衔接蛋白3复合物（AP-3）的HPS2型珍珠小鼠模型中的AT2未能在LB中积累可溶性酶过氧化物酶6（PRDX6）。此缺陷反映了PRDX6向LB的AP-3依赖性受损，因为珍珠鼠AT2细胞含有正常的总PRDX6含量。PRDX6对LB的AP-3依赖性靶向需要跨膜蛋白LIMP-2/SCARB2,这是一种已知的AP-3依赖性货物蛋白,其在其他细胞类型中充当溶酶体蛋白的载体。AP-3-或LIMP-2/SCARB2缺陷小鼠中LBPRDX6的消耗与层状体中的磷脂积累以及LB饱和磷脂酰胆碱的管腔内降解缺陷相关。此外，LIMP-2/SCARB2和PRDX6在体外和体内的蛋白质/蛋白质相互作用促进了AP-3依赖性LB靶向。我们的数据提供了AT2中LB成熟所需的AP-3依赖性货物蛋白的第一个证据，并表明PRDX6活性的丧失有助于发现HPS2患者LB磷脂稳态的致病性变化。
