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

Amika Singla, Alina Fedoseienko, Sai S. P. Giridharan, Brittany L. Overlee, Adam Lopez, Da Jia, Jie Song, Kayci Huff-Hardy, Lois Weisman, Ezra Burstein () and Daniel D. Billadeau ()
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Amika Singla: University of Texas Southwestern Medical Center
Alina Fedoseienko: College of Medicine, Mayo Clinic
Sai S. P. Giridharan: University of Michigan
Brittany L. Overlee: College of Medicine, Mayo Clinic
Adam Lopez: University of Texas Southwestern Medical Center
Da Jia: Sichuan University
Jie Song: University of Texas Southwestern Medical Center
Kayci Huff-Hardy: University of Texas Southwestern Medical Center
Lois Weisman: University of Michigan
Ezra Burstein: University of Texas Southwestern Medical Center
Daniel D. Billadeau: College of Medicine, Mayo Clinic

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12221-6

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