title: IKKα negatively regulates ASC-dependent inflammasome activation.
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.
authors.affiliation: 1] Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA [2] Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA [3].
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Martin
authors.affiliation: 1] Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA [2].
authors.forename: Chenhui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA.
authors.forename: Jami
authors.initials: J
authors.lastname: Willette-Brown
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Herjan
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Muhammet F
authors.initials: MF
authors.lastname: Gulen
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bulek
authors.affiliation: Comprehensive Cancer Center, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Franchi
authors.affiliation: Laboratory of Experimental Immunology, National Cancer Institute, Frederick, Maryland 21702, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Emad S
authors.initials: ES
authors.lastname: Alnemri
authors.affiliation: Department of Medicine, Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Goutham
authors.initials: G
authors.lastname: Narla
authors.affiliation: Department of Pediatrics and Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zhong
authors.affiliation: Department of Pediatric Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: James
authors.initials: J
authors.lastname: Thomas
authors.affiliation: Laboratory of Experimental Immunology, National Cancer Institute, Frederick, Maryland 21702, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Klinman
authors.affiliation: Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, San Diego, California 92093, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.affiliation: Comprehensive Cancer Center, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nuñez
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: George
authors.initials: G
authors.lastname: Dubyak
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA.
authors.forename: Yinling
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D021381:Protein Transport
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496566:Ikbke protein, mouse