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 () and Xiaoxia Li ()
Additional contact information
Bradley N. Martin: Lerner Research Institute, Cleveland Clinic Foundation
Chenhui Wang: Lerner Research Institute, Cleveland Clinic Foundation
Jami Willette-Brown: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute
Tomasz Herjan: Lerner Research Institute, Cleveland Clinic Foundation
Muhammet F. Gulen: Lerner Research Institute, Cleveland Clinic Foundation
Hao Zhou: Lerner Research Institute, Cleveland Clinic Foundation
Katarzyna Bulek: Lerner Research Institute, Cleveland Clinic Foundation
Luigi Franchi: Comprehensive Cancer Center, University of Michigan Medical School
Takashi Sato: Laboratory of Experimental Immunology, National Cancer Institute
Emad S. Alnemri: Kimmel Cancer Center, Thomas Jefferson University
Goutham Narla: Institute for Transformative Molecular Medicine, Case Western Reserve University
Xiao-Ping Zhong: Duke University Medical Center
James Thomas: Baylor College of Medicine
Dennis Klinman: Laboratory of Experimental Immunology, National Cancer Institute
Katherine A. Fitzgerald: University of Massachusetts Medical School
Michael Karin: Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California San Diego
Gabriel Nuñez: Comprehensive Cancer Center, University of Michigan Medical School
George Dubyak: Case Western Reserve University School of Medicine
Yinling Hu: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute
Xiaoxia Li: Lerner Research Institute, Cleveland Clinic Foundation

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5977

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