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

人体中的每个细胞表面都有一组特定的蛋白质，这些蛋白质与环境进行交换和沟通。通过内吞作用控制单个成分的周转对于调节细胞增殖的信号蛋白尤其重要，因此在癌症中是至关重要的。已知泛素修饰可通过网状蛋白载体触发内吞作用，并随后分选到内溶酶体内进行降解。我们现在有证据表明，另一种运输载体Caveolin-1(Caveolin-1)依赖于泛素选择分离酶Valosin-Holding Protein(VCP)/p97被内吞和分类。VCP及其辅因子Ufd1-Npl4在蛋白酶体降解方面的研究最好。相反，它与UBXD1辅助因子合作，靶向内体上的单一泛素化Cav1。一直以来，VCP突变，包括那些导致人类退行性疾病的突变，都专门阻止Cav1转运到内溶酶体。在拟议的项目中，我们希望揭示VCP介导的触发Cav1分选的分子反应并了解其调节。然后，我们想要探索VCP调节Cav1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。这项工作将阐明质膜上一层新的泛素依赖信号层，该信号层可能控制细胞内稳态和肿瘤发生，并将有助于阐明VCP在健康和疾病中的细胞相关性。

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.