Vps4 and the MVB sorting pathway

Vps4 和 MVB 排序路径

• 批准号: 7195800
• 负责人: MARKUS BABST
• 金额: $ 27.58万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-05 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7195800
• 关键词: ATP phosphohydrolase; Affect; Binding; Biochemical; Biological; Biological Models; Cell Communication; Cell Surface Proteins; Cell membrane; Cell physiology; Cells; Complex; Cytoplasm; Data; Development; Disease; Eukaryota; Eukaryotic Cell; Event; Genetic; HIV; HIV Infections; Immune response; Integral Membrane Protein; Lipids; Lumen of the Lysosome; Membrane; Modeling; Multiprotein Complexes; Multivesicular Body; Nutrient; Pathway interactions; Pharmaceutical Preparations; Process; Proteins; Rate; Reaction; Recruitment Activity; Regulation; Retroviridae; Saccharomycetales; Sorting - Cell Movement; Testing; Thinking; Vesicle; Viral; Virus Diseases; Work; base; endosome lumen; killings; particle; research study; trafficking; uptake

DESCRIPTION (provided by applicant): 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 MVB. 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. Vta1 appears to enhance the disassembly reaction that stimulates Vps4 ATPase activity. Fti1 works together with Vta1 in the activation of Vps4. Ist1 interferes with Vps4 function and Ist1 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 that eukaryotic cells modulate the activity of the MVB pathway by regulating the degradation rate of Ist1, thereby regulating the activity of Vps4.

描述（由申请人提供）：在真核生物中，“多囊泡体”（MVB）途径将跨膜蛋白和脂质递送到溶酶体的内腔中进行降解。因此，MVB 对于调节细胞表面蛋白组成和维持溶酶体功能至关重要。许多细胞功能，例如营养吸收、细胞通讯和免疫反应都依赖于 MVB。 MVB 分选机器执行独特的膜出芽事件，导致在内体腔中形成囊泡。 HIV 等逆转录病毒在病毒感染期间利用 MVB 机制，通过质膜上类似的膜出芽事件完成病毒颗粒的形成。因此，MVB 分选机已被公认为开发抗 HIV 感染新药的目标，这种疾病每年在全球夺去超过 200 万人的生命。几种多蛋白复合物（称为 ESCRT）在 MVB 上执行货物分选和囊泡形成。为了发挥其功能，可溶性 ESCRT 复合物从细胞质中招募，并依次在内体膜上组装，在那里它们将泛素化的货物分类成形成囊泡。为了完成囊泡的形成，ESCRT 复合物被 AAA 型 ATP 酶 Vps4 的活性分解。没有 Vps4 功能，ESCRT 机制仍保留在膜上，MVB 囊泡形成受到抑制。到目前为止，人们一直认为Vps4的反汇编功能是一个本构过程。然而，我们的初步研究已经确定了三种在多个水平上调节 Vps4 活性的蛋白质。 Vta1 似乎增强了刺激 Vps4 ATP 酶活性的分解反应。 Fti1 与 Vta1 一起激活 Vps4。 Ist1 干扰 Vps4 功能，并且 Ist1 活性本身似乎受到其稳定性的调节。基于这些发现，我们提出了一个修订模型，其中 ESCRT 复合物的 Vps4 依赖性分解代表了 MVB 途径中的关键调控步骤。我们提出真核细胞通过调节Ist1的降解速率来调节MVB通路的活性，从而调节Vps4的活性。