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

人体内的每个细胞表面都含有一组特定的蛋白质，这些蛋白质介导与环境的交换和沟通。通过内吞作用控制单个组分的周转对于调节细胞增殖的信号蛋白特别重要，因此在癌症中至关重要。已知泛素修饰通过网格蛋白载体引发内吞作用，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，小窝蛋白-1（Cav 1）是内吞和分选依赖于泛素选择性分离酶Valosin-Containing蛋白（VCP）/p97。VCP及其辅因子Ufd 1-Npl 4在蛋白酶体降解中研究得最好。相反，它与UBXD 1辅因子合作靶向内体上的单泛素化Cav 1。一致地，VCP突变，包括在人类中引起退行性疾病的那些，特异性地阻断Cavl向内溶酶体的运输。在拟议的项目中，我们希望揭示VCP介导的触发Cav 1分选的分子反应并了解其调节。然后，我们想探索VCP调节Cav 1的细胞相关性，并询问VCP是否更普遍地控制其他蛋白质（包括生长因子受体）的周转。这项工作将揭示质膜上一种新的泛素依赖性信号传导层，该层可能控制细胞内稳态和肿瘤发生，并将有助于澄清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.