NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria

Zhong, Zhenyu; Umemura, Atsushi; Sánchez-López, Elsa; Liang, Shuang; Shalapour, Shabnam; Wong, Jerry; He, Feng; Boassa, Daniela; Perkins, Guy; Ali, Shariq; McGeough, Matthew D.; Ellisman, Mark H.; Seki, Ekihiro; Gustafsson, Åsa B.; Hoffman, Hal M.; Diaz-Meco, Marı́a T.; Moscat, Jorge; Karin, Michael

doi:10.1016/j.cell.2015.12.057

Cited by 867 publications

(734 citation statements)

References 57 publications

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“…To determine the possible mechanism by which mitochondrial Nur77 induced mitophagy, we examined whether it interacted with p62/SQSTM1 (p62), which is implicated in the PINK1/Parkin mitophagic pathway (Geisler et al, 2010) and was more recently shown to mediate NF-κB induction of mitophagy (Zhong et al, 2016). CoIP assays showed that p62 strongly and specifically interacted with the slow-migrating, but not the fast-migrating, Nur77 band in the presence of celastrol and TNFα (Figure 7D).…”

Section: Resultsmentioning

confidence: 99%

Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy

et al. 2017

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SUMMARY Mitochondria play an integral role in cell death, autophagy, immunity, and inflammation. We previously showed that Nur77, an orphan nuclear receptor, induces apoptosis by targeting mitochondria. Here, we report that celastrol, a potent anti-inflammatory pentacyclic triterpene, binds Nur77 to inhibit inflammation and induce autophagy in a Nur77-dependent manner. Celastrol promotes Nur77 translocation from the nucleus to mitochondria, where it interacts with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase important for inflammatory signaling. The interaction is mediated by an LxxLL motif in TRAF2 and results not only in the inhibition of TRAF2 ubiquitination but also in Lys63-linked Nur77 ubiquitination. Under inflammatory conditions, ubiquitinated Nur77 resides at mitochondria, rendering them sensitive to autophagy, an event involving Nur77 interaction with p62/SQSTM1. Together, our results identify Nur77 as a critical intracellular target for celastrol and unravel a mechanism of Nur77-dependent clearance of inflamed mitochondria to alleviate inflammation.

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Section: Resultsmentioning

confidence: 99%

Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy

et al. 2017

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“…It has been shown that TLR2/6 activation induces p62 expression through the NADPH oxidase pathway (49). In addition, inflammatory NF-B activation in macrophages has been shown to induce p62 up-regulation, leading to mitophagy and thus limiting inflammasome activation (50). An NF-B response element has been identified in the p62 promoter (51).…”

Section: P62 and Nf-b In Chloroquine Resistancementioning

confidence: 99%

NF-κB Signaling Activation Induced by Chloroquine Requires Autophagosome, p62 Protein, and c-Jun N-terminal Kinase (JNK) Signaling and Promotes Tumor Cell Resistance

Yang¹,

Qiang²,

Sample

et al. 2017

Journal of Biological Chemistry

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Edited by George N. DeMartinoMacroautophagy (hereafter autophagy) is a catabolic cellular self-eating process by which unwanted organelles or proteins are delivered to lysosomes for degradation through autophagosomes. Although the role of autophagy in cancer has been shown to be context-dependent, the role of autophagy in tumor cell survival has attracted great interest in targeting autophagy for cancer therapy. One family of potential autophagy blockers is the quinoline-derived antimalarial family, including chloroquine (CQ). However, the molecular basis for tumor cell response to CQ remains poorly understood. We show here that Macroautophagy (hereafter autophagy) is an evolutionarily conserved cellular self-eating process, in which proteins or organelles are delivered to lysosomes for degradation (1, 2). Autophagy can inhibit or promote tumor development depending on the context (3-6). Autophagy deficiency has been reported to increase genome instability induced by oxidative stress or DNA damage, a well known factor for cancer initiation and progression (2,7,8). However, autophagy has been shown to promote cell survival and adaptation by protecting cells against various stress conditions such as anticancer treatment and unfavorable tumor microenvironments such as anoikis, starvation, and hypoxic or oxidative conditions (9, 10). Increasing evidence has indicated that inhibition of autophagy suppresses tumor growth, invasion, and metastasis (11-13). These findings suggest autophagy inhibition as an attractive new strategy to prevent and treat cancer.One of the representative autophagy inhibitors is chloroquine (CQ), 2 a lysosomotropic drug approved by the United States Food and Drug Administration for the prophylactic treatment of malaria (14, 15) and the management of lupus erythematosus and rheumatoid arthritis (16,17). Although it has several side effects such as skin rash, muscle damage, and vision problems (18,19), and an overdose can be lethal (20, 21), CQ has recently attracted considerable attention as an antitumor drug due to the potential biological effects on blocking autophagy in tumor cells (22)(23)(24). However, recent studies have shown that CQ exhibits its antitumor activity independent of autophagy inhibition (25), including normalizing the tumor vasculature (26). Several phase I and II clinical trials with CQ suggest that CQ can moderately improve the clinical activity of radiation therapy and several chemotherapeutics (22)(23)(24). In contrast, another antimalarial quinacrine is shown to induce cancer cell death through autophagy inhibition and p53-dependent inhibition of the oxidative pentose phosphate pathway (27).It is possible that the limited anticancer efficacy of CQ is caused by the induction of resistance pathways in tumor cells. However, how CQ induces resistance is unknown. In this study, we found that CQ induced NF-B activation through autophagosome accumulation, p62, and JNK signaling, which mediated CQ resistance in both squamous cell carcinoma (SCC) and melanoma cells. To determi...

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“…NF-κB activation will occur when it dissociates from IκBα that is a negative regulator of NF-κB [38]. In this study, our data demonstrated that bufalin treatment strongly suppressed the degradation of IκBα from NF-κB/IκBα complex, suggesting that NF-κB cannot translocate into the nucleus where it induces gene transcription by binding to the promoter of NF-κB responsive genes [39]. Similar findings indicated that bufalin significantly inhibited the activation of NF-κB in vivo by maintaining the level of IκBα, and reduced the nuclear translocation of NF-κB p65 [13].…”

Section: Discussionmentioning

confidence: 92%

Bufalin Inhibits the Inflammatory Effects in Asthmatic Mice through the Suppression of Nuclear Factor-Kappa B Activity

Zhakeer¹,

Hadeer²,

Tuerxun

et al. 2017

Pharmacology

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Asthma is an inflammatory airway disease characterized by increased infiltration of inflammatory cells into the airways and poor respiratory function. Bufalin is one of the biological ingredients obtained from Chansu. Bufalin was found to possess various pharmacological properties including anti-inflammatory activities. However, the effect of bufalin treatment on asthma has not yet been reported. Therefore, this study aimed to investigate the inhibitory effect of bufalin on asthmatic response in a murine model. A mouse asthma model was developed by ovalbumin (OVA) sensitization and challenge in the BALB/c mice. OVA-specific serum IgE and the levels of interleukin (IL)-4, IL-5, and IL-13 in bronchoalveolar lavage fluid (BALF) were determined by an enzyme-linked immunosorbent assay. Recruitment of inflammatory cells into BALF or lung tissues, and goblet cell hyperplasia were evaluated by histological staining. The expression levels of inhibitory subunit of nuclear factor-kappa B (NF-κB) alpha (IκBα) and phosphorylated p65 protein were measured by Western blot analyses. The results demonstrated that bufalin (5 and 10 mg/kg) markedly attenuated hyperresponsiveness, and strongly suppressed the OVA-induced increases of total inflammatory cells including macrophages, eosinophils, lymphocytes, and neutrophils in BALF. The levels of IL-4, IL-5, and IL-13 in BALF and OVA-specific IgE in serum were significantly reduced by bufalin. Histological staining of lung tissues showed that bufalin reduced inflammatory cell infiltration and goblet cell hyperplasia. The results of Western blotting indicated that bufalin suppressed the IκBα degradation from NF-κB, and reduced the level of phosphorylated p65 protein in the lung tissues. These data suggest that bufalin can exert its anti-inflammatory effects possibly through the inhibition of the NF-κB activity.

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NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria

Cited by 867 publications

References 57 publications

Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy

Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy

NF-κB Signaling Activation Induced by Chloroquine Requires Autophagosome, p62 Protein, and c-Jun N-terminal Kinase (JNK) Signaling and Promotes Tumor Cell Resistance

Bufalin Inhibits the Inflammatory Effects in Asthmatic Mice through the Suppression of Nuclear Factor-Kappa B Activity

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