Cdc42 helps cells take bigger bites

Phagocytic cells can eat larger items by adding more material to their plasma membrane, Mohammadi and Isberg show.

The motivation for the study was a puzzling observation about a key participant in phagocytosis, the Rho GTPase Cdc42, which spurs actin polymerization that enables the plasma membrane to encircle its target. In certain cases, cells with inactive Cdc42 can engulf small objects such as bacteria, but they can’t ingest larger items.

To find out why, Mohammadi and Isberg used RNAi to knock down Cdc42 in cultured cells. One possible explanation for the cells’ inability to eat large beads is that the absence of Cdc42 diminishes the activity of another GTPase involved in phagocytosis, Rac1. However, the researchers found that Rac1 activity was normal in Cdc42-lacking cells.

When the researchers observed forming phagosomes in cells that were trying to consume large beads, they noticed that membrane of the phagosome churned, a sign that new material was arriving. However, this membrane flux ended early in cells lacking Cdc42, suggesting that less membrane traveled to the surface of these cells.

Cdc42 therefore directs material to the plasma membrane, enabling cells to eat larger items. Cdc42 exerts its effect by stimulating the exocyst, a protein complex that helps shepherd vesicles to the plasma membrane. When cells are trying to eat big beads, the researchers discovered, Cdc42 temporarily latches onto the exocyst component Sec8. Moreover, reducing the activity of the exocyst protein Exo70 also impaired cells’ ability to engulf large objects. Still a mystery is how Cdc42 influences exocyst activity.