The project is to understand how IKKa regulates inflammasome activity in macrophages. Previously, we demonstrated that L-IkkaKA/KA mice develop spontaneous lung SCCs and that depleting macrophages prevents the lung SCCs, indicating that increased macrophages play an important role of macrophages in the lung SCC formation. Therefore, we further studied the function of IKKa in the activity of macrophages in L-IkkaKA/KA mice. The inflammasomes are multiprotein complexes that activate caspase-1 in response to infections and stress, resulting in the secretion of pro-inflammatory cytokines. Recently, we reported that IkB kinase a (IKKa) is a critical negative regulator of apoptosis-associated specklike protein containing a C-terminal caspase-activation-andrecruitment (CARD) domain (ASC)-dependent inflammasomes. IKKa controls the inflammasome at the level of the adaptor ASC, which interacts with IKKa in the nucleus of resting macrophages in an IKKa kinase-dependent manner. Loss of IKKa kinase activity results in inflammasome hyperactivation. Mechanistically, the downstream nuclear effector IKK-related kinase (IKKi) facilitates translocation of ASC from the nucleus to the perinuclear area during inflammasome activation. ASC remains under the control of IKKa in the perinuclear area following translocation of the ASC/IKKa complex. Signal 2 of NLRP3 activation leads to inhibition of IKKa kinase activity through the recruitment of PP2A, allowing ASC to participate in NLRP3 inflammasome assembly. Taken together, these findings reveal a IKKi-IKKa-ASC axis that serves as a common regulatory mechanism for ASC-dependent inflammasomes.
| Diamanti, Michaela A; Gupta, Jalaj; Bennecke, Moritz et al. (2017) IKK? controls ATG16L1 degradation to prevent ER stress during inflammation. J Exp Med 214:423-437 |
| Chen, Xin; Willette-Brown, Jami; Wu, Xueqiang et al. (2015) IKK? is required for the homeostasis of regulatory T cells and for the expansion of both regulatory and effector CD4 T cells. FASEB J 29:443-54 |
| Balkhi, Mumtaz Yaseen; Willette-Brown, Jami; Zhu, Feng et al. (2012) IKK?-mediated signaling circuitry regulates early B lymphopoiesis during hematopoiesis. Blood 119:5467-77 |
