IKKα negatively regulates ASC-dependent inflammasome activation

被引:0
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作者
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
机构
[1] Lerner Research Institute,Department of Immunology
[2] Cleveland Clinic Foundation,Department of Pathology
[3] Case Western Reserve University School of Medicine,Department of Pathology
[4] Cancer and Inflammation Program,Department of Biochemistry and Molecular Biology
[5] Center for Cancer Research,Department of Medicine
[6] National Cancer Institute,Department of Pediatrics and Immunology
[7] Comprehensive Cancer Center,Department of Pediatric Medicine
[8] University of Michigan Medical School,Division of Infectious Disease and Immunology, Department of Medicine
[9] Laboratory of Experimental Immunology,Departments of Pharmacology and Pathology
[10] National Cancer Institute,Department of Physiology and Biophysics
[11] Kimmel Cancer Center,undefined
[12] Thomas Jefferson University,undefined
[13] Institute for Transformative Molecular Medicine,undefined
[14] Case Western Reserve University,undefined
[15] Duke University Medical Center,undefined
[16] Baylor College of Medicine,undefined
[17] University of Massachusetts Medical School,undefined
[18] Laboratory of Gene Regulation and Signal Transduction,undefined
[19] School of Medicine,undefined
[20] University of California San Diego,undefined
[21] Case Western Reserve University School of Medicine,undefined
来源
Nature Communications | / 5卷
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摘要
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.
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