Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
J Cell Sci. 2022 Mar 1;135(5). doi: 10.1242/jcs.255026. Epub 2021 Apr 20.
Membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and late endosomes/lysosomes (LE/lys) are emerging as critical hubs for diverse cellular events, and changes in their extents are linked to severe neurological diseases. While recent studies show that the synaptotagmin-like mitochondrial-lipid-binding (SMP) domain-containing protein PDZD8 may mediate the formation of ER-LE/lys MCSs, the cellular functions of PDZD8 remain largely elusive. Here, we attempt to investigate the lipid transfer activities of PDZD8 and the extent to which its cellular functions depend on its lipid transfer activities. In accordance with recent studies, we demonstrate that PDZD8 is a protrudin (ZFYVE27)-interacting protein and that PDZD8 acts as a tether at ER-LE/lys MCSs. Furthermore, we discover that the SMP domain of PDZD8 binds glycerophospholipids and ceramides both in vivo and in vitro, and that the SMP domain can transport lipids between membranes in vitro. Functionally, PDZD8 is required for LE/lys positioning and neurite outgrowth, which is dependent on the lipid transfer activity of the SMP domain.
内质网（ER）和晚期内体/溶酶体（LE/lys）之间的膜接触位点（MCSs）正在成为多种细胞事件的关键枢纽，其范围的变化与严重的神经疾病有关。虽然最近的研究表明，突触结合蛋白样线粒体脂质结合（SMP）结构域包含蛋白 PDZD8 可能介导 ER-LE/lys MCSs 的形成，但 PDZD8 的细胞功能仍在很大程度上难以捉摸。在这里，我们试图研究 PDZD8 的脂质转移活性，以及其细胞功能在多大程度上依赖于其脂质转移活性。根据最近的研究，我们证明 PDZD8 是一个 protrudin（ZFYVE27）相互作用蛋白，PDZD8 作为 ER-LE/lys MCSs 的系链。此外，我们发现 PDZD8 的 SMP 结构域在体内和体外都结合甘油磷脂和神经酰胺，并且 SMP 结构域可以在体外在膜之间运输脂质。在功能上，PDZD8 对于 LE/lys 定位和神经突生长是必需的，这依赖于 SMP 结构域的脂质转移活性。
