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. 2011 Mar 24;7(3):e1001325. doi: 10.1371/journal.ppat.1001325

Figure 6. Model proposing a mechanism whereby Cif inhibits USP10 activity and reduces the apical membrane abundance of CFTR in polarized, human airway epithelial cells.

Figure 6

In the healthy state (i.e., not infected with P. aeruginosa), CFTR constitutively cycles in and out of the apical plasma membrane via trafficking through the early endosomal and recycling endosomal compartments. The secretion of Cif in OMV by P. aeruginosa redirects CFTR from the recycling pathway to the lysosomal, degradative pathway via an increase in the amount of multi-ubiquitinated CFTR. Cif inhibits the DUB activity of USP10 to increase the amount of ubiquitinated CFTR by stabilizing an inhibitory interaction between USP10 and G3BP1, and by decreasing the interaction between CFTR and USP10. It is still not known whether Cif directly or indirectly interacts with USP10 and G3BP1. These effects of Cif reduce the deubiquitination of CFTR in the early endosome and increase the lysosomal degradation of CFTR. Reduced apical membrane abundance of CFTR reduces Cl- secretion [3], [4], and is predicted to diminished mucociliary clearance, severely compromising the immune defenses of the lung [42], [43].