HECTD3 mediates TRAF3 polyubiquitination and type I interferon induction during bacterial infection

Li, Fubing; Yang, Li; Liang, Hongjun; Xu, Tao; Kong, Yanjie; Huang, Menghao; Xiao, Ji; Chen, Xi; Xia, Houjun; Wu, Yingying; Zhou, Zhongmei; Guo, Xiaomin; Hu, Chunmiao; Yang, Chunzhang; Xu, Chuanlong; Chen, Ceshi; Qi, Xiaopeng

doi:10.1172/jci120406

Cited by 47 publications

(52 citation statements)

References 55 publications

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“…Hectd3 did not promote RORγt polyubiquitination, but exerted control over RORγt level through regulating Stat3 activating phosphorylation at Y705, and thus promoting Th17 pathogenicity. We found Stat3 as a target of Hectd3 for non-degradative polyubiquitination in agreement with previous studies showing that Hectd3 mediates types of polyubiquitination not associated with proteasomal degradation but with signaling, controlling substrate activity on caspase-8 31 , caspase-9 32 , Malt1 30 (and this study), and TRAF3 33 . We found that Hectd3 mediates K27-linked polyubiquitin chains on Stat3 and identified K180, within the Stat3 coiled-coil domain, as the target for polyubiquitination, which was important for proper Stat3 Y705 phosphorylation and generation of RORγt + IL-17A hi Th17 cells.…”

Section: Discussionsupporting

confidence: 93%

“…In addition, Hectd3 was found to ubiquitinate several caspases, regulating survival of cancer cell lines 31,32 . Recently, Hectd3 was found to promote type I interferon (IFN) response in bone-marrow-derived macrophages through polyubiquitination of TRAF3, and this correlated with altered antibacterial response 33 . Malt1, an essential component of the Carma1-Bcl10-Malt1 (CBM) complex 34 , was found to be essential for Th17 pathogenicity in EAE through promoting nuclear translocation of p65 and inhibiting nuclear translocation of RelB 35,36 .…”

Section: Introductionmentioning

confidence: 99%

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Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation

Cho

Parthasarathy

et al. 2019

Nat Commun

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Polyubiquitination promotes proteasomal degradation, or signaling and localization, of targeted proteins. Here we show that the E3 ubiquitin ligase Hectd3 is necessary for pathogenic Th17 cell generation in experimental autoimmune encephalomyelitis (EAE), a mouse model for human multiple sclerosis. Hectd3-deficient mice have lower EAE severity, reduced Th17 program and inefficient Th17 cell differentiation. However, Stat3, but not RORγt, has decreased polyubiquitination, as well as diminished tyrosine-705 activating phosphorylation. Additionally, non-degradative polyubiquitination of Malt1, critical for NF-κB activation and Th17 cell function, is reduced. Mechanistically, Hectd3 promotes K27-linked and K29-linked polyubiquitin chains on Malt1, and K27-linked polyubiquitin chains on Stat3. Moreover, Stat3 K180 and Malt1 K648 are targeted by Hectd3 for non-degradative polyubiquitination to mediate robust generation of RORγt+IL-17Ahi effector CD4+ T cells. Thus, our studies delineate a mechanism connecting signaling related polyubiquitination of Malt1 and Stat3, leading to NF-kB activation and RORγt expression, to pathogenic Th17 cell function in EAE.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation

Cho

Parthasarathy

et al. 2019

Nat Commun

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“…Additionally, among common DEGs in stage I-II endometriosis, several of them are relative to inflammatory and/or infectious process. ZNF580 is potentially involved in the modulation of inflammatory process 141 ; DCAF15 is potentially involved in the immune surveillance 142 ; BANF1 is involved in the immunity against integration of foreign DNA and response to DNA damage 143 , and it is required to maintain undifferentiated phenotype of the stem cells 144 ; HECTD3 is associated to the modulation of host defense against infection 145 ; SSC5D, which is a soluble receptor produced by macrophages, T cells, and epithelial cells from placenta, is upregulated on infection and it has capacity to interact with bacteria 146 ; TEFB has a role in the autophagy and in the regulation of inflammasome 147 ; CD74 plays a role in the macrophage recruitment, adhesion and migration 148 . Despite the debatable utility of the biomarkers as noninvasive tool to diagnosis endometriosis 149,150 , these differences in transcript levels should be investigated further, at least as a driver to understand its pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome meta-analysis reveals differences of immune profile between eutopic endometrium from stage I-II and III-IV endometriosis independently of hormonal milieu

Poli-Neto

Meola

Silva

et al. 2020

Sci Rep

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Eutopic endometrium appears to be crucial for endometriosis development. Despite of the evident importance, data regarding the cellular microenvironment remain unclear. Our objective was to explore the tissue microenvironment heterogeneity, transcripts, and pathways that are enriched in all phases of the menstrual cycle by analysing publicly deposited data derived from whole transcriptome microarrays of eutopic endometria of women with and without endometriosis. A meta-analysis of the transcriptome microarrays was performed using raw data available from a public database. Eligibility criteria included eutopic endometrium samples from women with endometriosis and healthy controls without any pathological condition reported the presence of an adequately reported normal menstrual phase, and samples containing both glandular and stromal components. Raw data were processed using a robust multiarray average method to provide background correction, normalisation, and summarisation. The batch effect was estimated by principal variant component analysis and removed using an empirical Bayes method. Cellular tissue heterogeneity was inferred using the xCell package. Differentially expressed genes were identified based on a 5% adjusted p value and a 2.0-fold change. Pathways were identified by functional enrichment based on the Molecular Signatures Database, a p value of < 5%, and an FDR q value of ≤ 25%. Genes that were more frequently found in pathways were identified using leading edge analysis. In a manner independent of cycle phase, the subpopulations of activated dendritic cells, CD4 T effector memory phenotype cells, eosinophils, macrophages M1, and natural killer T cells (NKT) were all higher in stage I-II endometriosis compared to those in healthy controls. The subpopulations of M2 macrophages and natural killer T cells were elevated in eutopic endometriums from women with stage III-IV endometriosis, and smooth muscle cells were always more prevalent in healthy eutopic endometriums. Among the differently expressed genes, FOS, FOSB, JUNB, and EGR1 were the most frequently mapped within the interaction networks, and this was independent of stage and cycle phase. The enriched pathways were directly related to immune surveillance, stem cell self-renewal, and epithelial mesenchymal transition. PI3K AKT mTOR, TGF signalling, and interferon alpha/gamma responses were enriched exclusively in stage III-IV endometriosis. The cellular microenvironments and immune cell profiles were different between eutopic endometriums from women with stage I-II and stage III-IV endometriosis, and these differences were independent of the hormonal milieu. Specifically, a pro-inflammatory profile was predominant in stage I-II endometriosis, and M1-M2 polarization into eutopic endometrium may be crucial for the progression of the disease. The higher prevalence of NKT cells in eutopic endometriums from women with endometriosis that

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“…During bacterial infections, the E3 ligase HCTD3 adds K63-linked ubiquitin chains to TRAF3, which enhances the activation of the TBK1/IKKε complex and subsequent production of IFN-Is (73). Conversely, several deubiquitinases, including OTUB1, OTUB2, DUBA, and HSCARG, have been shown to downregulate RLR-mediated IFN-I production by removing K63-linked polyubiquitin chains from TRAF3 or TRAF6 [(74, 75), p. 1; (76)].…”

Section: The Role Of Trafs In Rig-i-like Receptor Signalingmentioning

confidence: 99%

The Evolving Role of TRAFs in Mediating Inflammatory Responses

et al. 2019

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TRAFs [tumor necrosis factor (TNF) receptor associated factors] are a family of signaling molecules that function downstream of multiple receptor signaling pathways and play a pivotal role in the biology of innate, and adaptive immune cells. Following receptor ligation, TRAFs generally function as adapter proteins to mediate the activation of intracellular signaling cascades. With the exception of TRAF1 that lacks a Ring domain, TRAFs have an E3 ubiquitin ligase activity which also contributes to their ability to activate downstream signaling pathways. TRAF-mediated signaling pathways culminate in the activation of several transcription factors, including nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs; e.g., ERK-1 and ERK-2, JNK, and p38), and interferon-regulatory factors (IRF; e.g., IRF3 and IRF7). The biological role of TRAFs is largely due to their ability to positively or negatively regulate canonical and non-canonical NF-κB signaling. While TRAF-mediated signaling regulates various immune cell functions, this review is focused on the recent advances in our knowledge regarding the molecular mechanisms through which TRAF proteins regulate, positively and negatively, inflammatory signaling pathways, including Toll–IL-1 receptors, RIG-I like receptors, and Nod-like receptors. The review also offers a perspective on the unanswered questions that need to be addressed to fully understand how TRAFs regulate inflammation.

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HECTD3 mediates TRAF3 polyubiquitination and type I interferon induction during bacterial infection

Cited by 47 publications

References 55 publications

Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation

Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation

Transcriptome meta-analysis reveals differences of immune profile between eutopic endometrium from stage I-II and III-IV endometriosis independently of hormonal milieu

The Evolving Role of TRAFs in Mediating Inflammatory Responses

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