TRAF6-mediated ubiquitination of NEMO requires p62/sequestosome-1

Zotti, Tiziana; Scudiero, Ivan; Settembre, Pio; Ferravante, Angela; Mazzone, P.; D’Andrea, Luca E.; Reale, Carla; Vito, Pasquale; Stilo, Romania

doi:10.1016/j.molimm.2013.10.015

Cited by 51 publications

(51 citation statements)

References 28 publications

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“…However, Keap1 recruitment to mycobacterial phagosomes seemed independent of p62 in the present study. We also found that knockdown of p62 showed a trend of reduced expression of TNF in line with other studies (47,48,52), and opposite from what we observed with Keap1 knockdown. We thus found no evidence that suggests that the effect seen on NF-κB signaling by Keap1/Cul3-Rbx1 might be dependent on p62.…”

Section: Discussionsupporting

confidence: 83%

“…p62 is well known for its role in protein aggregation and trafficking of ubiquitinated cargo to autophagy, and intricately linked to Keap1 (23,24,45). p62 is also reported to regulate various signaling events, including those activated by TNF, IL-1β and nerve growth factor receptors through scaffolding TRAF6 and atypical protein kinase C with these receptors in different cell types (46)(47)(48). Keap1 interacts with p62 (23)(24)(25), and p62 and LC3 are recruited to bacterial phagosomes to mediate autophagic clearance of the bacteria (49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

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Keap1 regulates inflammatory signaling in Mycobacterium avium -infected human macrophages

Awuh

Haug

Mildenberger

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Several mechanisms are involved in controlling intracellular survival of pathogenic mycobacteria in host macrophages, but how these mechanisms are regulated remains poorly understood. We report a role for Kelch-like ECH-associated protein 1 (Keap1), an oxidative stress sensor, in regulating inflammation induced by infection with Mycobacterium avium in human primary macrophages. By using confocal microscopy, we found that Keap1 associated with mycobacterial phagosomes in a time-dependent manner, whereas siRNA-mediated knockdown of Keap1 increased M. aviuminduced expression of inflammatory cytokines and type I interferons (IFNs). We show evidence of a mechanism whereby Keap1, as part of an E3 ubiquitin ligase complex with Cul3 and Rbx1, facilitates ubiquitination and degradation of IκB kinase (IKK)-β thus terminating IKK activity. Keap1 knockdown led to increased nuclear translocation of transcription factors NF-κB, IFN regulatory factor (IRF) 1, and IRF5 driving the expression of inflammatory cytokines and IFN-β. Furthermore, knockdown of other members of the Cul3 ubiquitin ligase complex also led to increased cytokine expression, further implicating this ligase complex in the regulation of the IKK family. Finally, increased inflammatory responses in Keap1-silenced cells contributed to decreased intracellular growth of M. avium in primary human macrophages that was reconstituted with inhibitors of IKKβ or TANK-binding kinase 1 (TBK1). Taken together, we propose that Keap1 acts as a negative regulator for the control of inflammatory signaling in M. avium-infected human primary macrophages. Although this might be important to avoid sustained or overwhelming inflammation, our data suggest that a negative consequence could be facilitated growth of pathogens like M. avium inside macrophages.Keap1 | human primary macrophages | infection | Mycobacterium avium | inflammation

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Keap1 regulates inflammatory signaling in Mycobacterium avium -infected human macrophages

Awuh

Haug

Mildenberger

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…SQSTM1 has been shown to be involved in the regulation of NF-κB signaling (Long et al, 2010; Wooten et al, 2005; Zotti et al, 2014). SQSTM1 is also shown to be important for NF-κB mediated tumorigenesis (Duran et al, 2008).…”

Section: Resultsmentioning

confidence: 99%

MELK Promotes Melanoma Growth by Stimulating the NF-κB Pathway

et al. 2017

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SUMMARY Melanoma accounts for over 80% of skin cancer-related deaths and current therapies provide only short-term benefit to patients. Here, we show in melanoma cells that maternal embryonic leucine zipper kinase (MELK) is transcriptionally upregulated by the MAP kinase pathway via transcription factor E2F1. MELK knockdown or pharmacological inhibition blocked melanoma growth and enhanced the effectiveness of BRAFV600E inhibitor against melanoma cells. To identify mediators of MELK function, we performed stable isotope labeling with amino acids in cell culture (SILAC) and identified 469 proteins that had downregulated phosphorylation after MELK inhibition. Remarkably, 139 of these proteins were previously reported as substrates of BRAF or MEK, demonstrating that MELK is an important downstream mediator of the MAPK pathway. Furthermore, we show that MELK promotes melanoma growth by activating NF-κB pathway activity via Sequestosome 1 (SQSTM1/p62). Collectively, these results underpin an important role for MELK in melanoma growth, downstream of the MAPK pathway.

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“…Previous studies revealed that p62 can act as an important intermediary in IL-1 signaling through TRAF6 interaction (31,32). An increased activity of TRAF proteins, due to the presence of CHQ, might regulate downstream signaling pathways.…”

Section: Lc3-ii P62/sqstm1 and Traf6 Expression Is Increased In Thementioning

confidence: 99%

Chloroquine Promotes IL-17 Production by CD4+ T Cells via p38-Dependent IL-23 Release by Monocyte-Derived Langerhans-like Cells

Said

Bock

Lajqi

et al. 2014

The Journal of Immunology

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Recent studies suggest a role for autophagy in the secretion of IL-1 cytokines regulating the development of inflammatory diseases. The antimalarial drug and autophagy/lysosome inhibitor chloroquine (CHQ) is considered as potential trigger of drug-induced or drug-aggravated psoriasis, in which Th17 cells sustain a persistent inflammation. In this study, we investigated the effect of CHQ on human monocyte-derived Langerhans-like cells (MoLC) and dendritic cells (MoDC) in response to IL-1β. The presence of CHQ reduced IL-12p70 release in both subsets, but surprisingly increased IL-6 production in MoDC and IL-23 in MoLC. Importantly, CHQ-treated MoLC promoted IL-17A secretion by CD4+ T cells and elevated RORC mRNA levels, whereas IFN-γ release was reduced. The dysregulation of IL-12 family cytokines in MoLC and MoDC occurred at the transcriptional level. Similar effects were obtained with other late autophagy inhibitors, whereas PI3K inhibitor 3-methyladenine failed to increase IL-23 secretion. The modulated cytokine release was dependent on IL-1 cytokine activation and abrogated by a specific IL-1R antagonist. CHQ elevated expression of TNFR-associated factor 6, a common intermediate in IL-1R and TLR-dependent signaling. Accordingly, treatment with Pam3CSK4 and CHQ enhanced IL-23 release in MoLC and MoDC. CHQ inhibited autophagic flux, confirmed by increased LC3-II and p62 expression, and activated ERK, p38, and JNK MAPK, but only inhibition of p38 abrogated IL-23 release by MoLC. Thus, our findings indicate that CHQ modulates cytokine release in a p38-dependent manner, suggesting an essential role of Langerhans cells and dendritic cells in CHQ-provoked psoriasis, possibly by promoting Th17 immunity.

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TRAF6-mediated ubiquitination of NEMO requires p62/sequestosome-1

Cited by 51 publications

References 28 publications

Keap1 regulates inflammatory signaling in Mycobacterium avium -infected human macrophages

Keap1 regulates inflammatory signaling in Mycobacterium avium -infected human macrophages

MELK Promotes Melanoma Growth by Stimulating the NF-κB Pathway

Chloroquine Promotes IL-17 Production by CD4+ T Cells via p38-Dependent IL-23 Release by Monocyte-Derived Langerhans-like Cells

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