Kumamoto University clarifies the regulatory mechanisms of innate immunity against bacterial infection at the atomic level

A research group led by Associate Professor Teruya Nakamura, Specially Appointed Professor Mikako Fujita, and Visiting Associate Professor Hiroshi Tateishi of the Faculty of Life Sciences at Kumamoto University, in collaboration with Specially Appointed Professor Jun-ichiro Inoue of the University of Tokyo Pandemic Preparedness, Infection and Advanced Research Center, and President Yuriko Yamagata of Shokei University Junior College, announced that they clarified the atomic-level molecular mechanism of regulation of TIFA-TRAF6 signaling by TIFAB, which is a signaling molecule that inhibits the function of TIFA in innate immune signaling (TIFA-TRAF6). The results were published in the March 5 issue of the U.S. scientific journal Proceedings of the National Academy of Sciences.

NF-κB is an important molecule involved in human innate immunity that triggers immune responses when activated by bacterial infection or other factors. TIFA and TRAF6 have been discovered as signaling molecules involved in NF-κB activation, and TIFA-TRAF6 signaling is a novel innate immunity signal against bacterial infection. To clarify how TIFAB binds to TIFA and suppresses signaling, the research group performed X-ray crystallography to determine the atomic-level three-dimensional structure of TIFAB bound to TIFA.

The result showed that one molecule each of TIFAB and TIFA formed a TIFA/TIFAB heterodimeric structure. This structure is similar to the homodimeric structure of TIFA. However, unlike TIFA, TIFAB does not have a phosphorylation site and cannot form an oligomeric structure like phosphorylated TIFA. Furthermore, TIFAB lacks a TRAF6 binding site and cannot bind TRAF6, which is important for signal transduction. This means that the TIFA/TIFAB heterodimeric structure is unable to activate the signal like the TIFA dimer. They also confirmed that although normal TIFAB inhibits NF-κB activation in response to bacterial infection, a TIFAB variant that was modified to be unable to bind TIFA by genetic recombination technology could not inhibit NF-κB activation in response to bacterial infection. This indicates that TIFAB-TIFA binding suppresses signaling by inhibiting TIFA homodimerization, which is essential for signal activation. Since TIFAB is implicated in myelodysplastic syndromes and acute myeloid leukemia, findings of this study may be useful in future studies on these diseases.

Nakamura said, "When we started this research project, I did not anticipate one-to-one TIFAB-TIFA binding as the mechanism of signal regulation. As further experiments were performed and this became clearer, I rediscovered the excitement of research."

Journal Information
Publication: Proceedings of the National Academy of Sciences of the United States of America
Title: TIFAB regulates the TIFA-TRAF6 signaling pathway involved in innate immunity by forming a heterodimer complex with TIFA
DOI: 10.1073/pnas.2318794121