title: NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria.
abstract: Nuclear factor κB (NF-κB), a key activator of inflammation, primes the NLRP3-inflammasome for activation by inducing pro-IL-1β and NLRP3 expression. NF-κB, however, also prevents excessive inflammation and restrains NLRP3-inflammasome activation through a poorly defined mechanism. We now show that NF-κB exerts its anti-inflammatory activity by inducing delayed accumulation of the autophagy receptor p62/SQSTM1. External NLRP3-activating stimuli trigger a form of mitochondrial (mt) damage that is caspase-1- and NLRP3-independent and causes release of direct NLRP3-inflammasome activators, including mtDNA and mtROS. Damaged mitochondria undergo Parkin-dependent ubiquitin conjugation and are specifically recognized by p62, which induces their mitophagic clearance. Macrophage-specific p62 ablation causes pronounced accumulation of damaged mitochondria and excessive IL-1β-dependent inflammation, enhancing macrophage death. Therefore, the "NF-κB-p62-mitophagy" pathway is a macrophage-intrinsic regulatory loop through which NF-κB restrains its own inflammation-promoting activity and orchestrates a self-limiting host response that maintains homeostasis and favors tissue repair.
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Umemura
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Elsa
authors.initials: E
authors.lastname: Sanchez-Lopez
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liang
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Shalapour
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Wong
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: He
authors.affiliation: National Center for Microscopy and Imaging Research, Center for Research in Biological Systems, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Boassa
authors.affiliation: National Center for Microscopy and Imaging Research, Center for Research in Biological Systems, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Guy
authors.initials: G
authors.lastname: Perkins
authors.affiliation: Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Syed Raza
authors.initials: SR
authors.lastname: Ali
authors.affiliation: Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: McGeough
authors.affiliation: National Center for Microscopy and Imaging Research, Center for Research in Biological Systems, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Ekihiro
authors.initials: E
authors.lastname: Seki
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Asa B
authors.initials: AB
authors.lastname: Gustafsson
authors.affiliation: Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.affiliation: Sanford-Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Diaz-Meco
authors.affiliation: Sanford-Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: karinoffice@ucsd.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D017382:Reactive Oxygen Species; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; C073701:Nfkb1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein