The inflammasomes are multiprotein complexes that activate caspase-1 in response to infections and stress, resulting in the secretion of pro-inflammatory cytokines. Here we report that IkappaB kinase alpha (IKKalpha) is a critical negative regulator of apoptosis-associated specklike protein containing a C-terminal caspase-activation-andrecruitment (CARD) domain (ASC)-dependent inflammasomes. IKKalpha controls the inflammasome at the level of the adaptor ASC, which interacts with IKKalpha in the nucleus of resting macrophages in an IKKalpha kinase-dependent manner. Loss of IKKalpha 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 IKKalpha in the perinuclear area following translocation of the ASC/IKKalpha complex. Signal 2 of NLRP3 activation leads to inhibition of IKKalpha kinase activity through the recruitment of PP2A, allowing ASC to participate in NLRP3 inflammasome assembly. Taken together, these findings reveal a IKKi-IKKalpha-ASC axis that serves as a common regulatory mechanism for ASC-dependent inflammasomes.