A Pseudomonas aeruginosa Toxin that Hijacks the Host Ubiquitin Proteolytic System

So this article was pretty cool. It was published in PLoS Pathogens and written by Bomberger et al. So often in people with respiratory infections, the Pseudomonas aeruginosa bacteria can also be found in the lungs of the infected patients. This bacteria secretes a toxin known as Cif. This toxin is known for decreasing the membrane expression of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR). CFTR is a giant protein channel that helps in releasing chloride out of the cell. This facilitates in the clearing of mucus from the airways and causing an immune response. The CFTR goes through a recycling process in which it gets tagged with ubiquitin, removed from the membrane, then either A) deubiquitinated and the protein returns to the membrane or B) the protein gets sent to a lysosome and then degraded.

The toxin Cif enters the host cell, and binds to USP10 (this is the protein within the cell which deubiquitinates the CFTR so that it can then be recycled back to the membrane). The binding of USP10 and Cif then disrupts the deubiquitination process so that CFTR remains ubuitinized. This is a very neat mechanism. It seems very simple, all the bacteria needs is to release a chemical, and have it bind within the host cell, and then the host cell is unable to clear the mucus from the airways, and the bacteria retains its nice environment to grow in.

Previously, this group had studied that USP10 deubiquitinates CFTR which decreases the amount of CFTR found in the membrane. They had not studied before how the Cif toxin plays a role in this pathway. I am always amazed at how a research group just whittles away and whittles away until the entire pathway is discovered.

Furthermore, the group showed that with the USP10 protein, it is specifically the Ras-GAP SH3 domain binding protein-1 (G3BP1) that binds in the presence of Cif. The presence of the Cif toxin was shown to both increase the binding of G3BP1 to USP10 and to decrease the interaction between USP10 and CFTR. So the authors not only discovered the pathway, but figured out the specific proteins and domains (at least on the USP10 protein) in which the interactions occur.

The paper had an incredible number of figures, that showed evidence for their conclusions. I thought it was a nicely written paper and that the figure of the mechanism was incredibly helpful.