IKKα negatively regulates ASC-dependent inflammasome activation.

Published

Journal Article

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 IκB kinase α (IKKα) is a critical negative regulator of apoptosis-associated specklike protein containing a C-terminal caspase-activation-andrecruitment (CARD) domain (ASC)-dependent inflammasomes. IKKα controls the inflammasome at the level of the adaptor ASC, which interacts with IKKα in the nucleus of resting macrophages in an IKKα kinase-dependent manner. Loss of IKKα 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 IKKα in the perinuclear area following translocation of the ASC/IKKα complex. Signal 2 of NLRP3 activation leads to inhibition of IKKα kinase activity through the recruitment of PP2A, allowing ASC to participate in NLRP3 inflammasome assembly. Taken together, these findings reveal a IKKi-IKKα-ASC axis that serves as a common regulatory mechanism for ASC-dependent inflammasomes.

Full Text

Duke Authors

Cited Authors

  • Martin, BN; Wang, C; Willette-Brown, J; Herjan, T; Gulen, MF; Zhou, H; Bulek, K; Franchi, L; Sato, T; Alnemri, ES; Narla, G; Zhong, X-P; Thomas, J; Klinman, D; Fitzgerald, KA; Karin, M; Nuñez, G; Dubyak, G; Hu, Y; Li, X

Published Date

  • September 30, 2014

Published In

Volume / Issue

  • 5 /

Start / End Page

  • 4977 -

PubMed ID

  • 25266676

Pubmed Central ID

  • 25266676

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

International Standard Serial Number (ISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms5977

Language

  • eng