Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome.

Takuma Misawa, MichihiroTakahama, Tatsuya Kozaki, Hanna Lee, Jian Zou, Tatsuya Saitoh & Shizuo Akira.

Nature immunology. (2013) 14, 454-460

Speaker: Chen-Chu Kao (高禎鞠)                                Time: 15:10~16:00, May 21, 2014

Commentator:Dr. Pei-Jane Tsai (蔡佩珍老師)            Place: Room 601

Abstract:

Inflammasomes are protein complexes assembled upon detecting pathogen infection or cell damage. Nod-like receptors (NLRs) and AIM2 (absent in melanoma-2) serve as platforms for clustering the inflammasome adapter molecule ASC (apoptosis-associated speck-like protein containing a CARD) and activation of caspase-1. Subsequently, activated caspase-1 promotes the secretion of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 (1). However, the regulatory mechanism of inflammasome is still complex. After screening a chemical compound library, the author observed that inhibitors of tubulin polymerization, such as colchicine and nocodazole, selectively suppressed the NLRP3 inflammasome activation. Resting NLRP3 was shown to be localized to endoplasmic reticulum while ASC was shown to be localized to mitochondria. Upon activation of inflammasome by MSU, both ASC and NLRP3 approached to the perinuclear region where they were co-localized with mitochondria and endoplasmic reticulum (2). MSU-induced activation of inflammasome led to aceytlation of α-tubulin, which in turn promoted the affinity andprocessivity of dynein motors. Therefore, acetylated α-tubulin caused dynein-dependent transport of ASC on mitochondria to NLRP3 on the endoplasmic reticulum. Inducers of the NLRP3inflammasome causeing mitochondrial damage led to a lower concentration of the coenzyme NAD⁺, which in turn inactivated NAD⁺-dependent sirtuin 2 (SIRT2). Furthermore, SIRT2 inactivation resulted in the accumulation of acetylated α-tubulin leading to the activation of NLRP3 inflammasome. Together, this work reveals a novel regulatory mechanism by which the microtubule machinery is required for NLRP3 inflammasome assembly and activation. Also this work provides insights into the effect of an α-tubulin inhibitor cochelcine on the treatment of inflammatory diseases like gout.

References:

1.         E. Latz, T. S. Xiao, A. Stutz, Activation and regulation of the inflammasomes. Nature Reviews Immunology13, 397-411 (2013)10.1038/nri3452).

2.         R. Zhou, A. S. Yazdi, P. Menu, J. Tschopp, A role for mitochondria in NLRP3 inflammasome activation. Nature469, 221-225 (2011); published online EpubJan 13 (10.1038/nature09663).