Bioscience

A Novel Mechanism for Cargo Release by Retrograde Motor Dynein/Dynactin

In collaboration with research groups led by Prof. Tian Changlin (University of Science and Technology of China) and Dr. Gong Weimin (Institute of Biophysics, CAS), Dr. Liu Jiajia and her colleagues at the Institute of Genetics and Developmental Biology, CAS found that PtdIns4P, a phospholipid enriched in Golgi membrane, plays an important role in SNX6 retromer-mediated cargo release at the trans-Golgi network (TGN). As cargo adaptor for dynein/dynactin, SNX6 binds to p150 Glued through its PX domain and to SNX1 through its BAR domain, linking the retromer complex and the retrograde motor at the cytoplasmic side of vesicular cargoes. The PX domain of SNX6 preferentially binds to PtdIns4P in vitro. Acute depletion of PtdIns4P from Golgi membrane causes peri-Golgi accumulation of the retromer cargo CI-MPR, and addition of PtdIns4P restores its Golgi localization. PtdIns4P specifically inhibits the protein-protein interaction between SNX6 and p150Glud, and incubation of PtdIns4P-containing liposomes with transport vesicles isolated from cells leads to dissociation of the motor complex from the retromer. This research is the first ever to demonstrate that an organelle-specific phospholipid can regulate precise unloading of vesicular cargoes at the target membrane through its regulation of motor-cargo interaction. In addition, it also shows that PtdIns4P plays a critical role in retrograde trafficking of tranferrin and its receptor, another dynein cargo, from endosomes to the endocytic recycling compartment (ERC), by regulating the interaction between SNX4 and the dynein light chain-interacting protein KIBRA, suggesting that phospholipid-regulated motor-cargo interaction provides a general mechanism for retrograde vesicular transport. These findings were published online on March 24, 2013 as a research article in Nature Cell Biology (DOI: 10.1038/ncb2710). Niu Yang, a graduate student with Dr. Liu, is the first author of the paper.