Endosomal PI(3)P regulation by the COMMD/CCDC22/CCDC93 (CCC) complex controls membrane protein recycling

• Published in: Nature communications 2019-09, Vol.10 (1), p.4271-17, Article 4271
• Main Authors: Singla, Amika, Fedoseienko, Alina, Giridharan, Sai S. P., Overlee, Brittany L., Lopez, Adam, Jia, Da, Song, Jie, Huff-Hardy, Kayci, Weisman, Lois, Burstein, Ezra, Billadeau, Daniel D.
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/89; 14/1; 14/19; 631/45; 631/80; Actin; Actins - metabolism; Adaptor Proteins, Signal Transducing - metabolism; Animals; Cargo; Cell Line, Tumor; Depletion; Endosomes - metabolism; HEK293 Cells; HeLa Cells; Humanities and Social Sciences; Humans; Lysosomes - metabolism; Membrane proteins; Membrane Proteins - metabolism; Membranes; Mice; Microfilament Proteins - metabolism; multidisciplinary; Nucleation; Phosphatidylinositol Phosphates - metabolism; Phosphorylation; Protein Tyrosine Phosphatases, Non-Receptor - metabolism; Proteins; Proteins - metabolism; Receptors; Recruitment; Recycling; RNA Interference; RNA, Small Interfering - genetics; Science; Science (multidisciplinary); Vesicular Transport Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12221-6

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. Recycling of proteins that have entered the endosome is essential to homeostasis. The COMMD/CCDC22/CCDC93 (CCC) complex is regulator of recycling but the molecular mechanisms are unclear. Here, the authors report that the CCC complex regulates endosomal recycling by maintaining PI3P levels on endosomal membranes.