| Autor: |
Singla A; Department of Internal Medicine, and Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Fedoseienko A; Division of Oncology Research and Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, MN, 55905, USA., Giridharan SSP; Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA., Overlee BL; Division of Oncology Research and Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, MN, 55905, USA., Lopez A; Department of Internal Medicine, and Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Jia D; Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, Division of Neurology, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, 610041, China., Song J; Department of Internal Medicine, and Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Huff-Hardy K; Department of Internal Medicine, and Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Weisman L; Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA., Burstein E; Department of Internal Medicine, and Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. ezra.burstein@utsouthwestern.edu., Billadeau DD; Division of Oncology Research and Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, MN, 55905, USA. billadeau.daniel@mayo.edu. |
| Abstrakt: |
Protein recycling through the endolysosomal system relies on molecular assemblies that interact with cargo proteins, membranes, and effector molecules. Among them, the COMMD/CCDC22/CCDC93 (CCC) complex plays a critical role in recycling events. While CCC is closely associated with retriever, a cargo recognition complex, its mechanism of action remains unexplained. Herein we show that CCC and retriever are closely linked through sharing a common subunit (VPS35L), yet the integrity of CCC, but not retriever, is required to maintain normal endosomal levels of phosphatidylinositol-3-phosphate (PI(3)P). CCC complex depletion leads to elevated PI(3)P levels, enhanced recruitment and activation of WASH (an actin nucleation promoting factor), excess endosomal F-actin and trapping of internalized receptors. Mechanistically, we find that CCC regulates the phosphorylation and endosomal recruitment of the PI(3)P phosphatase MTMR2. Taken together, we show that the regulation of PI(3)P levels by the CCC complex is critical to protein recycling in the endosomal compartment. |
