| dc.description.abstract | The NOD-like receptor protein NLRC5 inhibits TLR-induced NF-ҡB and viral
infection-mediated type I interferon signaling in vitro. In the first project, we generated
NLRC5 knockout mice to characterize the regulatory function of NLRC5. NLRC5
deficiency enhances Toll-like receptor-induced NF-ҡB signaling and type I IFN-mediated
antiviral immunity in mouse embryonic fibroblasts (MEFs). NLRC5
deficiency also increases proinflammatory cytokine response and antiviral immunity in
mouse immune cells. In addition, we confirmed that NLRC5 regulates the transcription
of MHC class I gene. Our findings indicate that NLRC5 is a regulator with multiple
functions by negatively regulating proinflammatory responses and positively regulating
MHC class I gene expression.
The inflammasome is a large protein complex that leads to apoptosis and
proinflammatory responses. One of the well-studied inflammasome transduces the
activation signal through NLRP3. NLRP3 inflammasome is known to be activated
through ASC oligomerization induced by varieties of stimulations; however, the
mechanism remains unknown. Some of the DDX family proteins have been reported to
sense DNA or RNA to activate type I IFN signaling pathway. By screening DDX family
proteins in 293T cells reconstituted with the inflammasome system, we found that
DDX46 enhanced NLRP3 inflammasome activity. Knockdown of DDX46 in THP-1
cells reduces inflammasome activity and IL-1β release after crystalline stimulations.
DDX46 is cleaved by activated caspase-3 after silica stimulation in mouse macrophages.
Furthermore, cleaved DDX46 interacts with the NLRP-ASC complex following silica stimulation. The positive regulatory role of cleaved DDX46 in silica-mediated NLRP3 inflammasome activation was confirmed in the 293T cell system by its strong ability to interact with ASC. Together, our findings indicate that cleaved DDX46 acts as a bridge to promote the interaction between NLRP3 and ASC after crystalline stimulation. | en |
