Vps4 and the MVB sorting pathway.

PoROVTIDI？ed. 在真核生物中，多囊泡小体(MVB)途径将跨膜蛋白和脂类运送到 用于降解的溶酶体的管腔。因此，MVB对于调节细胞表面是必不可少的。 蛋白质组成和维持溶酶体功能。多种细胞功能，如营养素 摄取、细胞通讯和免疫反应依赖于MVB。MVB分拣机械 执行独特的膜萌发事件，导致囊泡形成进入管腔 内生体。逆转录病毒，如艾滋病毒，在病毒感染期间利用MVB机制完成形成 通过在质膜上的类似的膜萌发事件，病毒颗粒。因此，MVB排序 机制已被确认为抗击艾滋病毒感染的新药开发的目标，a 每年导致全球200多万人死亡的疾病。几种多蛋白复合体，称为 在MYB，执行货物分类和囊泡形成。为了执行它们的功能，可溶的 ESCRT复合体从细胞质中招募，并顺序地组装在内体膜上 在那里他们将无处不在的货物分类形成囊泡。为了完成囊泡的形成，ESCRT 通过AAA型ATPase Vps4的活性来分解复合体。如果没有Vps4函数， ESCRT机制保留在膜上，MVB囊泡的形成被抑制。到目前为止，它已经 有人认为Vps4的解体功能是一个本构过程。然而，我们的初步调查 研究已经确定了三种在不同水平上调节Vps4活性的蛋白质。Vtal似乎 增强刺激Vps4 ATPase活性的拆解反应。FTIL与VTAL在 Vps4的激活。Ist1干扰Vps4功能，Istl活动本身似乎受其调节 稳定性。基于这些发现，我们提出了一个修正的模型，在该模型中，依赖于Vps4的拆卸 ESCRT复合体代表了MVB途径中的关键调控步骤。我们认为 细胞通过调节Istl的降解率来调节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.