The findings, published by investigators led by Jack Elias in the journal Nature Communications, appeared in the article “IL-13Rα2 Uses TMEM219 In Chitinase 3-Like-1-Induced Signalling And Effector Responses.”
Previous research from Elias and colleagues found an inflammatory protein, IL13Rα2, was associated with the activation of disease-related pathways when stimulated by another protein, called CHI3L1. Although IL13Rα2 and CHI3L1 normally have a protective role against lung injury and work to promote tissue repair, when in excessive levels they contribute to the development of IPF, lung cancer, and asthma.
Now, the researchers found that these two proteins sometimes join with a third, the protein TMEM219. Using different experiments, the researchers showed that the three proteins are not only located in the same places within cells, but also bind to each other. This three-way interaction activates disease-related pathways.
Using both mouse and human cells, the team observed that the inhibition or depletion of TMEM219 significantly reduced the activity of both CHI3L1 and IL13Rα2, supporting their hypothesis that the presence of this third protein triggers the disease-related pathways under the regulation of the two other proteins.
Indeed, the toxic effect exerted by the higher-than-usual levels of both CHI3L1 and IL13Rα2, found in IPF and lung cancer, was found to be significantly lower in mouse lungs when TMEM219 was blocked or removed by the scientists.
These results suggest a new approach to treating these diseases, that of targeting TMEM219 to block it from working with the other two proteins to activate disease-related pathways. The researchers already have tested antibodies against CHI3L1 and IL13Rα2 in mice, and now are developing antibodies against TMEM219, to either manipulate that protein or prevent it from binding to the others.
“Let’s say you want to block the functioning of a receptor [in a pathway],” Chang Min Lee, the study’s first author, said in a news release. “You don’t know what the consequences will be if you block IL13Rα2 and you don’t know what the consequences will be if you get rid of TMEM219, but if the pathway you are trying to block requires both proteins, you have the ability to choose between the proteins in making a drug that blocks the receptor. You can pick the blocking approach that has the lowest toxicity for the patient.”