Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity

Li, Xia; Zhang, Qian; Ding, Yuanyuan; Liu, Yiqi; Zhao, Dezhi; Zhao, Kai; Shen, Qicong; Liu, Xingguang; Zhu, Xuhui; Li, Nan; Cheng, Zhongyi; Fan, Guoping; Wang, Qingqing; Cao, Xuetao

doi:10.1038/ni.3464

Cited by 168 publications

(126 citation statements)

References 53 publications

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“…HDAC4, HDAC5 and HDAC9 or its splicing variant MITR are the class IIa HDACs more frequently overexpressed in LMS. A condition not limited to this tumor type, as testified by recent studies [43–47]. …”

Section: Discussionmentioning

confidence: 71%

The co-existence of transcriptional activator and transcriptional repressor MEF2 complexes influences tumor aggressiveness

et al. 2017

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The contribution of MEF2 TFs to the tumorigenic process is still mysterious. Here we clarify that MEF2 can support both pro-oncogenic or tumor suppressive activities depending on the interaction with co-activators or co-repressors partners. Through these interactions MEF2 supervise histone modifications associated with gene activation/repression, such as H3K4 methylation and H3K27 acetylation. Critical switches for the generation of a MEF2 repressive environment are class IIa HDACs. In leiomyosarcomas (LMS), this two-faced trait of MEF2 is relevant for tumor aggressiveness. Class IIa HDACs are overexpressed in 22% of LMS, where high levels of MEF2, HDAC4 and HDAC9 inversely correlate with overall survival. The knock out of HDAC9 suppresses the transformed phenotype of LMS cells, by restoring the transcriptional proficiency of some MEF2-target loci. HDAC9 coordinates also the demethylation of H3K4me3 at the promoters of MEF2-target genes. Moreover, we show that class IIa HDACs do not bind all the regulative elements bound by MEF2. Hence, in a cell MEF2-target genes actively transcribed and strongly repressed can coexist. However, these repressed MEF2-targets are poised in terms of chromatin signature. Overall our results candidate class IIa HDACs and HDAC9 in particular, as druggable targets for a therapeutic intervention in LMS.

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Section: Discussionmentioning

confidence: 71%

The co-existence of transcriptional activator and transcriptional repressor MEF2 complexes influences tumor aggressiveness

et al. 2017

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“…Other than Tet2, Tet3 and Dnmt3a have been recently reported to modulate gene expression in macrophages and control antiviral responses (Li et al, 2016; Xue et al, 2016). DNMT3A is also frequently mutated in HSCs, whose ablation leads to HSC expansion and inhibition of differentiation (Cullen and Goodell, 2015).…”

Section: Discussionmentioning

confidence: 99%

The DNA Methylcytosine Dioxygenase Tet2 Sustains Immunosuppressive Function of Tumor-Infiltrating Myeloid Cells to Promote Melanoma Progression

et al. 2017

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Summary Ten-Eleven-Translocation-2 (Tet2) is a DNA methylcytosine dioxygenase that functions as a tumor suppressor in hematopoietic malignancies. In this study, we revealed a role for Tet2 in sustaining the immunosuppressive function of tumor-tissue myeloid cells. We found that Tet2 expression is increased in intratumoral myeloid cells both in mouse models of melanoma and in melanoma patients, and that this increased expression is dependent on an IL-1R-MyD88 pathway. Ablation of Tet2 in myeloid cells suppressed melanoma growth in vivo, and shifted the immunosuppressive gene expression program in tumor-associated macrophages to a proinflammatory one, with a concomitant reduction of the immunosuppressive function. This resulted in increased numbers of effector T cells in the tumor, and T cell depletion abolished the reduced tumor growth observed upon myeloid-specific deletion of Tet2. Our findings reveal a non-cell-intrinsic, tumor-promoting function for Tet2, and suggest that Tet2 may present a therapeutic target for the treatment of non-hematologic malignancies.

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“…IL-6, TNF-α and IFN-β cytokines were detected with ELISA kits according to the manufacturer's protocols50.…”

Section: Methodsmentioning

confidence: 99%

E3 ligase FBXW7 is critical for RIG-I stabilization during antiviral responses

et al. 2017

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Viruses can escape from host recognition by degradation of RIG-I or interference with the RIG-I signalling to establish persistent infections. However, the mechanisms by which host cells stabilize RIG-I protein for avoiding its degradation are largely unknown. We report here that, upon virus infection, the E3 ubiquitin ligase FBXW7 translocates from the nucleus into the cytoplasm and stabilizes RIG-I. FBXW7 interacts with SHP2 and mediates the degradation and ubiquitination of SHP2, thus disrupting the SHP2/c-Cbl complex, which mediates RIG-I degradation. When infected with VSV or influenza A virus, FBXW7 conditional knockout mice (Lysm+FBXW7f/f) show impaired antiviral immunity. FBXW7-deficient macrophages have decreased RIG-I protein levels and type-I interferon signalling. Furthermore, PBMCs from RSV-infected children have reduced FBXW7 mRNA levels. Our results identify FBXW7 as an important interacting partner for RIG-I. These findings provide insights into the function of FBXW7 in antiviral immunity and its related clinical significance.

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Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity

Cited by 168 publications

References 53 publications

The co-existence of transcriptional activator and transcriptional repressor MEF2 complexes influences tumor aggressiveness

The co-existence of transcriptional activator and transcriptional repressor MEF2 complexes influences tumor aggressiveness

The DNA Methylcytosine Dioxygenase Tet2 Sustains Immunosuppressive Function of Tumor-Infiltrating Myeloid Cells to Promote Melanoma Progression

E3 ligase FBXW7 is critical for RIG-I stabilization during antiviral responses

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