Regulation of endosome function by the AAA-ATPase Vps4

细胞对来自环境的许多信号作出反应。一些信号告诉细胞生长和分裂，另一些信号告诉细胞休息。这些信号通常在健康细胞中处于平衡状态。为了防止细胞以不受控制的方式生长和分裂并形成癌症，有一些机制可以关闭生长信号。一种机制是破坏负责生长信号的蛋白质。这涉及将信号蛋白从发生信号的膜一侧翻转（通过称为多泡体或MVB的过程）到不能发生信号并且信号蛋白可以降解的另一侧。有趣的是，最近发现一些病毒（包括艾滋病病毒）使用相同的MVB分选机制从感染的细胞中逃逸。然而，这种病毒并没有经历MVB分选到内部隔室并被降解，而是能够使用相同的机制从细胞中翻转出来。MVB分选是如何发生的尚不清楚，但该机制在进化过程中得到了保护，甚至像酵母这样的微生物也可以对蛋白质进行MVB分选。我们正在研究MVB分选机制的一个组成部分，称为Vps4，它存在于人类细胞和酵母细胞中。由于人类Vps4和酵母Vps4似乎以相同的方式发挥作用，并且由于强大的分子遗传学方法可以在酵母中用于阐明蛋白质如何发挥作用（其中一些在人类细胞中是不可能的），因此我们正在使用酵母研究Vps4功能。一旦我们了解了酵母Vps4的工作原理，我们将能够测试人类Vps4是否以同样的方式工作。了解MVB分选机制将为我们提供细胞如何防止不受控制的生长和分裂的信息，也可能帮助我们找到预防艾滋病感染的方法。

Cells respond to many signals from the environment. Some signals tell cells to grow and divide and other signals tell cells to rest. These signals are usually in balance in healthy cells. To prevent cells from growing and dividing in an uncontrolled manner and forming a cancer, there are mechanisms to turn off signals for growth. One mechanism is to destroy the proteins responsible for growth signalling. This involves flipping (by a process called multivesicular body, or MVB, sorting) the signalling protein from one side of the membrane where signalling occurs to the other side where signalling cannot occur and where the signalling protein can be degraded. Interestingly, it has recently been discovered that some viruses (including the AIDS virus) use the same MVB sorting mechanisms to escape from infected cells. Instead of undergoing MVB sorting into an internal compartment and getting degraded, however, the virus is able to use the same mechanism to flip out of the cell. How MVB sorting occurs is not known, but the mechanism has been conserved through evolution and even microbes like yeast can perform MVB sorting of proteins. We are investigating a component of the MVB sorting mechanism known as Vps4 which is present in both human cells and in yeast cells. Since the human Vps4 and yeast Vps4 seem to function in the same way, and since powerful molecular genetic approaches can be used in yeast to elucidate how proteins function (some of which are not possible with human cells), we are using yeast to investigate Vps4 function. Once we understand how the yeast Vps4 works, we will be able to test if human Vps4 works the same way. Understanding the MVB sorting mechanism will give us information on how cells prevent uncontrolled growth and division and may also help us find ways of preventing AIDS infection.