Researchers discovered that the CYLD protein turns off pathogen-induced inflammatory responses mediated by the myeloid differentiation factor 88 (MyD88), thereby preventing uncontrolled inflammation from damaging tissues and eventually inducing chronic obstructive pulmonary disease (COPD). The study, titled “Deubiquitinase CYLD acts as a negative regulator for bacterium NTHi-induced inflammation by suppressing K63-linked ubiquitination of MyD88,” was published in the Proceedings of the National Academy of Sciences journal.
The research team at Georgia State University used a nontypeable Haemophilus influenzae (NTHi), the leading bacterium of COPD and ear infections, to understand how MyD88, a crucial protein in the host defense response against invading pathogens, is regulated.
“Here we found for the first time that a protein called CYLD plays a critical role in controlling the pathogen-induced inflammatory response by targeting MyD88. More specifically, we found CYLD inhibits bacteria-induced signaling of MyD88 by deactivating MyD88 at a critical amino acid, lysine 231,” said Dr. Jian-Dong Li, director of the Institute for Biomedical Sciences at Georgia State, a Georgia Research Alliance Eminent Scholar in Inflammation and Immunity, and study lead author, in a university news release.
CYLD was found to be capable of blocking NTHi bacterium activation of MyD88 in mice and human epithelial cells. The results showed that the body can control the inflammatory response triggered by an infectious agent through CYLD activity, which directly interacts with MyD88 to prevent uncontrolled inflammatory responses (an established phenotype that leads to tissue damage and underlies multiple diseases, including COPD).
“MyD88 has been shown to mediate the host defense response against many microbial pathogens. Therefore, understanding how the signaling of this protein is tightly regulated likely could lead to the development of novel therapeutics for many diseases. Because we know this is a key therapeutic target, we can develop therapeutics specifically against this target in the future—for instance, treatments that increase the production of the brake-pedal protein CYLD,” added Dr. Li.
Steroids are currently used as anti-inflammatory agents, however, their long-term used is associated with serious side effects, such as increased risk of infections, liver damage, increased blood pressure, and a slow healing of wounds. The results from the present study suggest that CYLD is a potential new anti-inflammatory strategy to be tested in future studies.