Histone deacetylase isoforms regulate innate immune responses by deacetylating mitogen-activated protein kinase phosphatase-1

Jeong, Youngtae; Du, Ronghui; Zhu, Xiaolei; Yin, Shasha; Wang, Jian; Cui, Hengmi; Cao, Wangsen; Lowenstein, Charles J.

doi:10.1189/jlb.1013565

Cited by 76 publications

(85 citation statements)

References 68 publications

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“…Here we reveal a crucial and previously unsuspected link between the ISR and the gene expression programs underpinning melanoma biology regulated by MITF; microenvironmental signals, including glutamine limitation and TNFα, converge to inhibit eIF2B, leading to a block in MITF translation as well as ATF4 expression and direct repression of MITF transcription. Although we did not examine the molecular mechanism underpinning repression of MITF by ATF4, it is likely that it occurs either by displacement of the MITF promoter activator CREB that shares a related DNA-binding motif or via recruitment of a repressive cofactor, as has been observed at the Apelin gene promoter (Jeong et al 2014). The role of ATF4 and translation reprogramming in resistance to adoptive T-cell therapy is clinically relevant.…”

Section: Discussionmentioning

confidence: 98%

Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma

et al. 2017

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The intratumor microenvironment generates phenotypically distinct but interconvertible malignant cell subpopulations that fuel metastatic spread and therapeutic resistance. Whether different microenvironmental cues impose invasive or therapy-resistant phenotypes via a common mechanism is unknown. In melanoma, low expression of the lineage survival oncogene microphthalmia-associated transcription factor (MITF) correlates with invasion, senescence, and drug resistance. However, how MITF is suppressed in vivo and how MITF-low cells in tumors escape senescence are poorly understood. Here we show that microenvironmental cues, including inflammationmediated resistance to adoptive T-cell immunotherapy, transcriptionally repress MITF via ATF4 in response to inhibition of translation initiation factor eIF2B. ATF4, a key transcription mediator of the integrated stress response, also activates AXL and suppresses senescence to impose the MITF-low/AXL-high drug-resistant phenotype observed in human tumors. However, unexpectedly, without translation reprogramming an ATF4-high/MITF-low state is insufficient to drive invasion. Importantly, translation reprogramming dramatically enhances tumorigenesis and is linked to a previously unexplained gene expression program associated with anti-PD-1 immunotherapy resistance. Since we show that inhibition of eIF2B also drives neural crest migration and yeast invasiveness, our results suggest that translation reprogramming, an evolutionarily conserved starvation response, has been hijacked by microenvironmental stress signals in melanoma to drive phenotypic plasticity and invasion and determine therapeutic outcome.

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Section: Discussionmentioning

confidence: 98%

Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma

et al. 2017

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“…Western blotting and coimmunoprecipitation assays were performed essentially as described before (16) with the antibodies indicated below at a predetermined dilution.…”

Section: Methodsmentioning

confidence: 99%

Toll-Like Receptor Signaling Induces Nrf2 Pathway Activation through p62-Triggered Keap1 Degradation

Yin

Cao

2015

Molecular and Cellular Biology

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Toll-like receptors (TLRs) induce inflammation and tissue repair through multiple signaling pathways. The Nrf2 pathway plays a key role in defending against the tissue damage incurred by microbial infection or inflammation-associated diseases. The critical event that mediates TLR-induced Nrf2 activation is still poorly understood. In this study, we found that lipopolysaccharide (LPS) and other Toll-like receptor (TLR) agonists activate Nrf2 signaling and the activation is due to the reduction of Keap1, the key Nrf2 inhibitor. TLR signaling-induced Keap1 reduction promoted Nrf2 translocation from the cytoplasm to the nucleus, where it activated transcription of its target genes. TLR agonists modulated Keap1 at the protein posttranslation level through autophagy. TLR signaling increased the expression of autophagy protein p62 and LC3-II and induced their association with Keap1 in the autophagosome-like structures. We also characterized the interaction between p62 and Keap1 and found that p62 is indispensable for TLR-mediated Keap1 reduction: TLR signaling had no effect on Keap1 if cells lacked p62 or if cells expressed a mutant Keap1 that could not interact with p62. Our study indicates that p62-mediated Keap1 degradation through autophagy represents a critical linkage for TLR signaling regulation of the major defense network, the Nrf2 signaling pathway.

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“…HDAC is involved in the upregulation or downregulation of gene expression. Jeong et al 24 indicated that HDAC1, 2 and 3 deacetylate MAPK-phosphatase-1, thereby increasing MAPK signaling and innate immune signaling and resulting in inflammatory responses; thus, these factors may be potential therapeutic targets for inflammatory diseases. Our results showing that, upon exposure to allergic mediators, the levels of HDAC1 increased are in line with the reports of Jeong et al Based on the notion that butyrate is an HDAC inhibitor and the fact that C. butyricum produces butyrate, we treated allergic mice with C. butyricum together with SIT.…”

Section: Trek1 and Gut Barrier Function H Huang Et Almentioning

confidence: 99%

Regulation of TWIK-related potassium channel-1 (Trek1) restitutes intestinal epithelial barrier function

Huang

Liu

et al. 2015

Cell Mol Immunol

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The disruption of epithelial barrier integrity is an important factor in the pathogenesis of various immune disorders. However, the restitution of the compromised barrier functions is difficult. This study investigates the regulation of TWIK-related potassium channel-1 (Trek1) in the restitution of intestinal epithelial barrier functions. The human colon epithelial cell line T84 was cultured in monolayers and used to observe epithelial barrier functions in vitro. An intestinal allergy mouse model was created. Cytokine levels were determined by enzyme-linked immunosorbent assay and western blotting. The results showed that Trek1 deficiency induced T84 monolayer barrier disruption. Allergic responses markedly suppressed the expression of Trek1 in the intestinal epithelia via activating the mitogen-activated protein kinase pathways and increasing the expression of histone deacetylase-1. The inhibition of histone deacetylase-1 by sodium butyrate or the administration of a butyrate-producing probiotic (Clostridium butyricum) restored the intestinal epithelial barrier functions and markedly enhanced the effect of antigen-specific immunotherapy. The data suggest that Trek1 is required for the maintenance of intestinal epithelial barrier integrity. Allergic responses induce an insufficiency of Trek1 expression in the intestinal epithelia. Trek1 expression facilitates the restoration of intestinal epithelial barrier functions in an allergic environment.

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Histone deacetylase isoforms regulate innate immune responses by deacetylating mitogen-activated protein kinase phosphatase-1

Cited by 76 publications

References 68 publications

Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma

Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma

Toll-Like Receptor Signaling Induces Nrf2 Pathway Activation through p62-Triggered Keap1 Degradation

Regulation of TWIK-related potassium channel-1 (Trek1) restitutes intestinal epithelial barrier function

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