NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria

Zhong, Z et al. Cell 164: 896–910, 2016

Speaker: Fu-Yu Chan (詹復宇)                                    Time: 14:10~15:00

Commentator: Chih-Peng Chang(張志鵬 老師)         Place: Room 601

Abstract:

Nuclear factor kB (NF-kB), an activator of inflammation, primes the NLRP3-inflammasome for activation by inducing pro-IL-1b and NLRP3 expression. NF-kB, however, also has anti-inflammatory functions, and its activity is needed for preventing premature and excessive NLRP3-inflammasome activation in macrophages through by autophagy. In this study, the authors showed that NF-kB 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. 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-1b-dependent inflammation, enhancing macrophage death. Therefore, the NF-κB-p62-mitophagy pathway is a macrophage-intrinsic regulatory loop through which NF-kB restrains its own inflammation-promoting activity and orchestrates a self-limiting host response that maintains homeostasis and favors tissue repair.

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