Chair of Biochemistry I, University of Würzburg, Biocenter, Am Hubland, 97074 Würzburg, Germany.
Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Josef-Schneider-Straße 2, 97080 Würzburg, Germany.
Mol Biol Cell. 2023 Dec 1;34(13):ar126. doi: 10.1091/mbc.E23-06-0237. Epub 2023 Sep 27.
The endocytic pathway is of central importance for eukaryotic cells, as it enables uptake of extracellular materials, membrane protein quality control and recycling, as well as modulation of receptor signaling. While the ATPase p97 (VCP, Cdc48) has been found to be involved in the fusion of early endosomes and endolysosomal degradation, its role in endocytic trafficking is still incompletely characterized. Here, we identify myoferlin (MYOF), a ferlin family member with functions in membrane trafficking and repair, as a hitherto unknown p97 interactor. The interaction of MYOF with p97 depends on the cofactor PLAA previously linked to endosomal sorting. Besides PLAA, shared interactors of p97 and MYOF comprise several proteins involved in endosomal recycling pathways, including Rab11, Rab14, and the transferrin receptor CD71. Accordingly, a fraction of p97 and PLAA localizes to MYOF-, Rab11-, and Rab14-positive endosomal compartments. Pharmacological inhibition of p97 delays transferrin recycling, indicating that p97 promotes not only the lysosomal degradation, but also the recycling of endocytic cargo.
内吞作用途径对于真核细胞至关重要，因为它能够摄取细胞外物质、进行膜蛋白质量控制和回收，以及调节受体信号转导。尽管 ATP 酶 p97（VCP，CDC48）已被发现参与早期内体融合和内体溶酶体降解，但它在胞吞作用中的作用仍未完全阐明。在这里，我们鉴定了肌球蛋白（MYOF），一种在膜运输和修复中具有功能的 ferlin 家族成员，作为一种迄今未知的 p97 相互作用蛋白。MYOF 与 p97 的相互作用依赖于以前与内体分选相关的辅助因子 PLAA。除了 PLAA 之外，p97 和 MYOF 的共同相互作用蛋白包括几个参与内体回收途径的蛋白，包括 Rab11、Rab14 和转铁蛋白受体 CD71。因此，一部分 p97 和 PLAA 定位于 MYOF、Rab11 和 Rab14 阳性内体区室。p97 的药理学抑制延迟了转铁蛋白的回收，表明 p97 不仅促进了溶酶体降解，还促进了内吞货物的回收。
