%0 Journal %B Cell %D 2016 %T NF-kappaB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria %A Zhong, Z. %A Umemura, A. %A Sanchez-Lopez, E. %A Liang, S. %A Shalapour, S. %A Wong, J. %A He, F. %A Boassa, D. %A Perkins, G. %A Ali, S. R. %A McGeough, M. D. %A Ellisman, M. H. %A Seki, E. %A Gustafsson, A. B. %A Hoffman, H. M. %A Diaz-Meco, M. T. %A Moscat, J. %A Karin, M. %N 5 %P 896-910 %V 164 %7 2016/02/27 %8 Feb 25 %@ 0092-8674 %1 10.1016/j.cell.2015.12.057 %X Nuclear factor kappaB (NF-kappaB), a key activator of inflammation, primes the NLRP3-inflammasome for activation by inducing pro-IL-1beta and NLRP3 expression. NF-kappaB, however, also prevents excessive inflammation and restrains NLRP3-inflammasome activation through a poorly defined mechanism. We now show that NF-kappaB 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-1beta-dependent inflammation, enhancing macrophage death. Therefore, the "NF-kappaB-p62-mitophagy" pathway is a macrophage-intrinsic regulatory loop through which NF-kappaB restrains its own inflammation-promoting activity and orchestrates a self-limiting host response that maintains homeostasis and favors tissue repair. %G eng %+ 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. 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. Division of Gastroenterology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. 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. Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. 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. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA. Sanford-Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. 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. %M 26919428 %! NF-kappaB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria