Deubiquitinase CYLD acts as a negative regulator for bacterium NTHi-induced inflammation by suppressing K63-linked ubiquitination of MyD88

Significance Despite the critical role for myeloid differentiation factor 88 (MyD88) in mediating pathogen-induced innate and adaptive immune responses, how functional activity of MyD88 is tightly controlled remains unknown. Among various types of posttranslational modification, ubiquitination and deubiquitination of host signaling molecules play an important role in tightly regulating immune response. However, inducible ubiquitination, in particular proteolysis-independent polyubiquitination as well as deubiquitination of MyD88, remains largely unclear. Here, we demonstrate that deubiquitinase CYLD negatively regulates MyD88-mediated inflammation by directly interacting with MyD88 and deubiquitinating nontypeable Haemophilus influenzae -induced lysine 63-linked polyubiquitination of MyD88. Thus, our studies may not only bring insights into the negative regulation of Toll-like receptor–MyD88-dependent signaling but may also lead to the development of a previously unidentified therapeutic strategy for uncontrolled inflammation.