Haas Alexander K, Fuchs Evelyn, Kopajtich Robert, Barr Francis A
Max-Planck Institute of Biochemistry, Department of Cell Biology, Am Klopferspitz 18, D-82152 Martinsried, Germany.
Nat Cell Biol. 2005 Sep;7(9):887-93. doi: 10.1038/ncb1290. Epub 2005 Aug 7.
Rab-family GTPases are conserved regulators of membrane trafficking that cycle between inactive GDP-bound and activated GTP-bound states. A key determinant of Rab function is the lifetime of the GTP-bound state. As Rabs have a low intrinsic rate of GTP hydrolysis, this process is under the control of GTP-hydrolysis-activating proteins (GAPs). Due to the large number of Rabs and GAPs that are encoded by the human genome, it has proven difficult to assign specific functional relationships to these proteins. Here, we identify a Rab5-specific GAP (RabGAP-5), and show that RN-Tre (previously described as a Rab5 GAP) acts on Rab41. RabGAP-5 overexpression triggers a loss of the Rab5 effector EEA1 from endosomes and blocks endocytic trafficking. By contrast, depletion of RabGAP-5 results in increased endosome size, more endosome-associated EEA1, and disrupts the trafficking of EGF and LAMP1. RabGAP-5 therefore limits the amount of activated Rab5, and thereby regulates trafficking through endosomes.
Rab家族GTP酶是膜运输的保守调节因子，在无活性的GDP结合状态和活化的GTP结合状态之间循环。Rab功能的一个关键决定因素是GTP结合状态的寿命。由于Rabs的GTP水解内在速率较低，这个过程受GTP水解激活蛋白（GAPs）的控制。由于人类基因组编码了大量的Rabs和GAPs，已证明难以确定这些蛋白质的特定功能关系。在这里，我们鉴定出一种Rab5特异性GAP（RabGAP-5），并表明RN-Tre（先前被描述为一种Rab5 GAP）作用于Rab41。RabGAP-5的过表达引发内体中Rab5效应器EEA1的丢失，并阻断内吞运输。相比之下，RabGAP-5的缺失导致内体大小增加、更多与内体相关的EEA1，并扰乱表皮生长因子（EGF）和溶酶体相关膜蛋白1（LAMP1）的运输。因此，RabGAP-5限制了活化Rab5的量，从而调节通过内体的运输。
