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PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation.

ABSTRACT: The NLRP3 inflammasome, which has been linked to human inflammatory diseases, is activated by diverse stimuli. How these stimuli activate NLRP3 is unknown. Here we show that different NLRP3 stimuli lead to disassembly of the trans-Golgi network (TGN). NLRP3 is recruited to the dispersed TGN (dTGN) through ionic bonding between its conserved polybasic region and negatively charged phosphatidylinositol-4-phosphate (PtdIns4P) on the dTGN. The dTGN then serves as a scaffold for NLRP3 aggregation into multiple puncta, leading to polymerization of the adaptor protein ASC, thereby activating the downstream signalling cascade. Disruption of the interaction between NLRP3 and PtdIns4P on the dTGN blocked NLRP3 aggregation and downstream signalling. These results indicate that recruitment of NLRP3 to dTGN is an early and common cellular event that leads to NLRP3 aggregation and activation in response to diverse stimuli.

SUBMITTER: Chen J

PROVIDER: S-EPMC9402428 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation.

Chen Jueqi J Chen Zhijian J ZJ

Nature 20181128 7734

The NLRP3 inflammasome, which has been linked to human inflammatory diseases, is activated by diverse stimuli. How these stimuli activate NLRP3 is unknown. Here we show that different NLRP3 stimuli lead to disassembly of the trans-Golgi network (TGN). NLRP3 is recruited to the dispersed TGN (dTGN) through ionic bonding between its conserved polybasic region and negatively charged phosphatidylinositol-4-phosphate (PtdIns4P) on the dTGN. The dTGN then serves as a scaffold for NLRP3 aggregation int ...[more]

PMID: 30487600

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Project description:Paclitaxel is a chemotherapeutic drug commonly used to treat different types of cancer. In addition to its antitumor effect, paclitaxel is also known to promote Toll-like receptor (TLR) 4-dependent inflammatory responses, which may lower its chemotherapeutic efficacy. However, it remains unclear whether paclitaxel is able to affect inflammasome signaling in myeloid or cancer cells. Therefore, we examined the potential effect of paclitaxel on the activation of an inflammasome complex by examining caspase-1 activation and interleukin (IL)-1β secretion in bone marrow-derived macrophages (BMDMs). The results showed that treatment with paclitaxel alone or following LPS priming failed to trigger the secretion of active caspase-1 and IL-1β from BMDMs. However, paclitaxel could induce robust activation of caspase-1 in BMDMs in the presence of NLRP3 inflammasome-activating signal 2, such as ATP or nigericin. This paclitaxel/ATP-mediated inflammasome activation was completely abrogated in Nlrp3-deficient macrophages. Mechanistically, paclitaxel treatment induced robust activation of the TLR4 signaling cascade, including phosphorylation of IκB and JNK and upregulation of proinflammatory cytokine mRNA levels in a TLR4-dependent manner. In contrast, paclitaxel treatment alone did not induce mitochondrial damages such as the loss of the mitochondrial membrane potential and production of mitochondrial ROS. These findings suggest that paclitaxel can drive the priming of signal-mediated events for NLRP3 activation but not a second signal-triggered phenomenon such as mitochondrial damage. This suggestion was supported by the observations that paclitaxel treatment caused robust IL-1β production in macrophages in the presence of cell-free medium derived from growth of injured cells and also in the spleen of mice. Collectively, our data strongly indicate that paclitaxel is able to facilitate the activation of NLRP3 inflammasome signaling in a certain physiological environment.

Dataset Information

PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation.

Publications

PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation.

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