VCP/p97-governed sorting of mono-ubiquitinated proteins in the endocytic pathway

内吞途径中 VCP/p97 控制的单泛素化蛋白排序

• 批准号: 197350480
• 负责人: Professor Dr. Hemmo Meyer
• 金额: --
• 依托单位: Abteilung Molekularbiologie I
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/197350480?language=en
• 关键词: VCP; p97; governed; sorting; mono

Each cell in the human body contains a specific set of proteins on the surface that mediate exchange and communication with the environment. Controlled turnover of individual components by endocyto-sis is particularly important for signaling proteins that regulate cell proliferation and are therefore criti-cal in cancer. Ubiquitin modification is known to trigger endocytosis by clathrin carriers and subse-quent sorting to endolysosomes for degradation. We now have evidence that another transport carrier, Caveolin-1 (Cav1) is endocytosed and sorted dependent on the ubiquitin-selective segregase Valosin-Containing Protein (VCP)/p97. VCP with its cofactor Ufd1-Npl4 is best studied in proteasomal degradation. In contrast, it cooperates with the UBXD1 cofactor to target mono-ubiquitinated Cav1 on endosomes. Consistently, VCP mutations including those that cause a degenerative disease in humans specifically block Cav1 trafficking to endolysosomes. In the proposed project, we wish to reveal the VCP-mediated molecular reaction that triggers sorting of Cav1 and understand its regulation. We then want to explore the cellular relevance of Cav1 regulation by VCP and ask whether VCP more generally controls turnover of other proteins including growth factor receptors. This work will shed light on a novel layer of ubiquitin-dependent signaling at the plasma membrane that may govern cellular homoeostasis and tumorigenesis, and will help to clarify the cellular relevance of VCP in health and disease.

人体的每个细胞表面都含有一组特定的蛋白质，可介导与环境的交换和沟通。通过内吞作用控制各个成分的周转对于调节细胞增殖的信号蛋白尤其重要，因此在癌症中至关重要。已知泛素修饰会触发网格蛋白载体的内吞作用，并随后分选至内溶酶体进行降解。我们现在有证据表明，另一种转运载体 Caveolin-1 (Cav1) 的内吞和分选依赖于泛素选择性分离酶 Valosin 含蛋白 (VCP)/p97。 VCP 及其辅因子 Ufd1-Npl4 在蛋白酶体降解方面得到了最好的研究。相反，它与 UBXD1 辅因子合作，靶向内体上的单泛素化 Cav1。一致的是，VCP 突变（包括导致人类退行性疾病的突变）会特异性阻止 Cav1 转运至内溶酶体。在拟议的项目中，我们希望揭示 VCP 介导的触发 Cav1 排序的分子反应并了解其调控。然后我们想要探索 VCP 对 Cav1 调节的细胞相关性，并询问 VCP 是否更普遍地控制包括生长因子受体在内的其他蛋白质的周转。这项工作将揭示质膜上一层新的泛素依赖性信号传导，该信号传导可能控制细胞稳态和肿瘤发生，并将有助于阐明 VCP 在健康和疾病中的细胞相关性。