IKKα negatively regulates ASC-dependent inflammasome activation

Bradley N. Martin, Chenhui Wang, Jami Willette-Brown, Tomasz Herjan, Muhammet F. Gulen, Hao Zhou, Katarzyna Bulek, Luigi Franchi, Takashi Sato, Emad S. Alnemri, Goutham Narla, Xiao Ping Zhong, James Thomas, Dennis Klinman, Katherine A. Fitzgerald, Michael Karin, Gabriel Nuñez, George Dubyak, Yinling Hu, Xiaoxia Li

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article number4977
JournalNature Communications
Volume5
DOIs
StatePublished - 2014

Fingerprint

Inflammasomes
Chemical activation
activation
Phosphotransferases
effectors
secretions
nuclei
macrophages
regulators
apoptosis
infectious diseases
assembly
proteins
Personnel Selection
Multiprotein Complexes
Caspase 1
Macrophages
Caspases
Apoptosis
Cytokines

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Martin, B. N., Wang, C., Willette-Brown, J., Herjan, T., Gulen, M. F., Zhou, H., ... Li, X. (2014). IKKα negatively regulates ASC-dependent inflammasome activation. Nature Communications, 5, [4977]. https://doi.org/10.1038/ncomms5977

IKKα negatively regulates ASC-dependent inflammasome activation. / Martin, Bradley N.; Wang, Chenhui; Willette-Brown, Jami; Herjan, Tomasz; Gulen, Muhammet F.; Zhou, Hao; Bulek, Katarzyna; Franchi, Luigi; Sato, Takashi; Alnemri, Emad S.; Narla, Goutham; Zhong, Xiao Ping; Thomas, James; Klinman, Dennis; Fitzgerald, Katherine A.; Karin, Michael; Nuñez, Gabriel; Dubyak, George; Hu, Yinling; Li, Xiaoxia.

In: Nature Communications, Vol. 5, 4977, 2014.

Research output: Contribution to journalArticle

Martin, BN, Wang, C, Willette-Brown, J, Herjan, T, Gulen, MF, Zhou, H, Bulek, K, Franchi, L, Sato, T, Alnemri, ES, Narla, G, Zhong, XP, Thomas, J, Klinman, D, Fitzgerald, KA, Karin, M, Nuñez, G, Dubyak, G, Hu, Y & Li, X 2014, 'IKKα negatively regulates ASC-dependent inflammasome activation', Nature Communications, vol. 5, 4977. https://doi.org/10.1038/ncomms5977
Martin BN, Wang C, Willette-Brown J, Herjan T, Gulen MF, Zhou H et al. IKKα negatively regulates ASC-dependent inflammasome activation. Nature Communications. 2014;5. 4977. https://doi.org/10.1038/ncomms5977
Martin, Bradley N. ; Wang, Chenhui ; Willette-Brown, Jami ; Herjan, Tomasz ; Gulen, Muhammet F. ; Zhou, Hao ; Bulek, Katarzyna ; Franchi, Luigi ; Sato, Takashi ; Alnemri, Emad S. ; Narla, Goutham ; Zhong, Xiao Ping ; Thomas, James ; Klinman, Dennis ; Fitzgerald, Katherine A. ; Karin, Michael ; Nuñez, Gabriel ; Dubyak, George ; Hu, Yinling ; Li, Xiaoxia. / IKKα negatively regulates ASC-dependent inflammasome activation. In: Nature Communications. 2014 ; Vol. 5.
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