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Regulation of polycystin expression, maturation and trafficking

机译：调节多囊酶表达，成熟和贩运

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The major autosomal dominant polycystic kidney disease (ADPKD) genes, PKD1 and PKD2, are wildly expressed at the organ and tissue level. PKD1 encodes polycystin 1 (PC1), a large membrane associated receptor-like protein that can complex with the PKD2 product, PC2. Various cellular locations have been described for both PC1, including the plasma membrane and extracellular vesicles, and PC2, especially the endoplasmic reticulum (ER), but compelling evidence indicates that the primary cilium, a sensory organelle, is the key site for the polycystin complex to prevent PKD. As with other membrane proteins, the ER biogenesis pathway is key to appropriately folding, performing quality control, and exporting fully folded PC1 to the Golgi apparatus. There is a requirement for binding with PC2 and cleavage of PC1 at the GPS for this folding and export to occur. Six different monogenic defects in this pathway lead to cystic disease development, with PC1 apparently particularly sensitive to defects in this general protein processing pathway. Trafficking of membrane proteins, and the polycystins in particular, through the Golgi to the primary cilium have been analyzed in detail, but at this time, there is no clear consensus on a ciliary targeting sequence required to export proteins to the cilium. After transitioning though the trans-Golgi network, polycystin-bearing vesicles are likely sorted to early or recycling endosomes and then transported to the ciliary base, possibly via docking to transition fibers (TF). The membrane-bound polycystin complex then undergoes facilitated trafficking through the transition zone, the diffusion barrier at the base of the cilium, before entering the cilium. Intraflagellar transport (IFT) may be involved in moving the polycystins along the cilia, but data also indicates other mechanisms. The ciliary polycystin complex can be ubiquitinated and removed from cilia by internalization at the ciliary base and may be sent back to the plasma membrane for recycling or to lysosomes for degradation. Monogenic defects in processes regulating the protein composition of cilia are associated with syndromic disorders involving many organ systems, reflecting the pleotropic role of cilia during development and for tissue maintenance. Many of these ciliopathies have renal involvement, likely because of faulty polycystin signaling from cilia. Understanding the expression, maturation and trafficking of the polycystins helps understand PKD pathogenesis and suggests opportunities for therapeutic intervention.
机译：主要的常染色体显性多囊肾病（ADPKD）基因，PKD1和PKD2在器官和组织水平上野外表达。 PKD1编码多囊素1（PC1），一种膜相关的受体样蛋白，可与PKD2产品，PC2复合。已描述各种细胞位置，包括血浆膜和细胞外囊泡，并且PC2，尤其是内质网（ER），但令人信服的证据表明初级纤毛，一种感觉细胞器是多囊蛋白复合物的关键部位防止PKD。与其他膜蛋白一样，ER生物发生途径是适当折叠，执行质量控制和将完全折叠的PC1输出到GOLGI装置的关键。需要与PC2结合，并在GPS下裂解PC1，以进行这种折叠和出口。该途径中的六种不同的单一缺陷导致囊性疾病发育，PC1显然对该一般蛋白质加工途径中的缺陷特别敏感。通过贩运膜蛋白，特别是通过GOLGI通过GOLGI进行详细分析，但此时，在将蛋白质导出到纤毛蛋白所需的睫状靶向序列上没有明显共识。在过渡后，虽然Trans-GOLGI网络，可能将多环酮囊泡分类为早期或回收内体，然后通过对接至过渡纤维（TF）来转运到睫状体基质。然后在进入纤毛之前经历膜结合的多囊络合物，通过过渡区进行促进的流动区，在纤毛鎓碱的底部的扩散屏障。 Intraflaglear传输（IFT）可能涉及沿纤毛的多环酮移动，但数据也表明了其他机制。睫状多环络合物可以通过在睫状碱中的内化中染上并从纤毛中除去，并且可以被送回质膜以再循环或溶酶体进行降解。调节纤毛蛋白质组成的方法中的单一缺陷与涉及许多器官系统的综合组织疾病有关，反映了纤毛在发育过程中和组织维持期间的血浆作用。许多这些纤维化病有肾脏受累，可能是因为来自纤毛的缺陷的多囊素信号传导。了解多环酮的表达，成熟和贩运有助于了解PKD发病机制，并表明治疗干预机会。

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