Vps4 and the MVB sorting pathway.

PoROvVTIDi？ED。 在真核生物中，“多泡体”（MVB）途径将跨膜蛋白和脂质输送到 溶酶体的内腔进行降解。因此，MVB对于调节细胞表面是必需的 蛋白质组成和维持溶酶体功能。许多细胞功能，如营养 摄取、细胞通讯和免疫反应取决于MVB。MVB分选机 执行一个独特的膜出芽事件，这导致囊泡形成到管腔中， 核内体逆转录病毒如HIV在病毒感染期间利用MVB机制完成形成 病毒颗粒通过类似的膜出芽事件在质膜。因此，MVB排序 这一机制已被公认为是开发抗艾滋病毒感染新药的目标， 这种疾病每年在全世界造成200多万人死亡。几种多蛋白复合物，称为 ESCRT，在MYB执行货物分类和囊泡形成。为了发挥其功能，可溶性 ESCRT复合物从细胞质中募集并顺序组装在内体膜上 在那里它们将泛素化的货物分类形成囊泡。为了完成囊泡形成，ESCRT 复合物被AAA型ATP酶Vps4的活性分解。如果没有Vps4功能， ESCRT机器保留在膜上，MVB囊泡形成受到抑制。到目前为止， 以往认为Vps4的拆卸功能是一个本构过程。然而，我们的初步 研究已经鉴定了在几个水平上调节Vps4活性的三种蛋白质。Vtal似乎 增强刺激Vps4 ATP酶活性的分解反应。Ftil与Vtal合作， 激活Vps4。Istl干扰Vps4功能，并且Istl活性本身似乎受其调节。 稳定基于这些发现，我们提出了一个修正模型，其中Vps4依赖的拆卸 ESCRT复合物代表了MVB通路中的关键调节步骤。 细胞通过调节Istl的降解速率来调节MVB途径的活性，从而调节 Vps4的活性。

PoROvVTIDi¿ED. In eukaryotes, the 'multivesicular body' (MVB) pathway delivers transmembrane proteins and lipids into the lumen of the lysosome for degradation. As a consequence, MVBs are essential for regulating cell surface protein composition and maintaining lysosomal function. Numerous cellular functions, such as nutrient uptake, cell communication and immune response are dependent on MVBs. The MVB sorting machinery performs a unique membrane budding event, which results in the formation of vesicles into the lumen of the endosome. Retroviruses such as HIV co-opt the MVB machinery during viral infection to complete formation of viral particles via a similar membrane budding event at the plasma membrane. Therefore, the MVB sorting machinery has been recognized as a target for the development of new drugs combating HIV infection, a disease that kills more than 2 million people per year worldwide. Several multiprotein complexes, called the ESCRTs, execute cargo sorting and vesicle formation at the MYB. To perform their function, the soluble ESCRT complexes are recruited from the cytoplasm and sequentially assemble on the endosomal membrane where they sort ubiquitinated cargo into forming vesicles. To complete vesicle formation, the ESCRT complexes are disassembled by the activity of the AAA-type ATPase Vps4. Without Vps4 function, the ESCRT machinery remains on the membrane and MVB vesicle formation is inhibited. Up until now, it had been thought that the disassembly function of Vps4 was a constitutive process. However, our preliminary studies have identified three proteins that regulate the activity of Vps4 on several levels. Vtal appears to enhance the disassembly reaction that stimulates Vps4 ATPase,activity. Ftil works together with Vtal in the activation of Vps4. Istl interferes with Vps4 function and Istl activity itself appears to be regulated by its stability. Based on these findings we propose a revised model in which the Vps4-dependent disassembly of the ESCRT complexes represents a key regulatory step within the MVB pathway.We propose thateukaryotic cells modulate the activity of the MVB pathway by regulating the degradation rate of Istl, thereby regulating the activity of Vps4.