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

Nat Commun. 2019 Sep 19;10(1):4271. doi: 10.1038/s41467-019-12221-6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Line, Tumor
  • Endosomes / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lysosomes / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Microfilament Proteins / metabolism*
  • Phosphatidylinositol Phosphates / metabolism*
  • Phosphorylation
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism
  • Proteins / metabolism*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Vesicular Transport Proteins / metabolism*

Substances

  • Actins
  • Adaptor Proteins, Signal Transducing
  • CCDC22 protein, human
  • CCDC93 protein, human
  • COMMD1 protein, human
  • Membrane Proteins
  • Microfilament Proteins
  • Phosphatidylinositol Phosphates
  • Proteins
  • RNA, Small Interfering
  • Vesicular Transport Proteins
  • WASH protein, human
  • phosphatidylinositol 3-phosphate
  • MTMR2 protein, human
  • Protein Tyrosine Phosphatases, Non-Receptor