Mechanism by which TRAF6 Participates in the Immune Regulation of Autoimmune Diseases and Cancer

Wang, Jingjing; Wu, Xianguo; Jiang, Mengyu; Tai, Guihua

doi:10.1155/2020/4607197

Cited by 24 publications

(18 citation statements)

References 141 publications

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“…This pathway has been described to contribute to all stages of liver disease progression, from initial liver injury through inflammation and fibrosis to cirrhosis and hepatocellular carcinoma (HCC) (13–15). Moreover, TRAF6 Mediated Induction of proinflammatory cytokines is a key driving force of proinflammatory and profibrogenic responses in NASH (16) and has been described as a possible contributor to progression to HCC (17). TLR4 signaling repertoire is involved in a variety of liver injury including that induced by NASH, which has been shown to play a key role during fibrogenesis in preclinical models of NAFLD (18), as wells as to enhance TGF-β signaling (19).…”

Section: Resultsmentioning

confidence: 99%

ChemPert: mapping between chemical perturbation and transcriptional response for non-cancer cells

Zheng

Okawa

Bravo

et al. 2022

Preprint

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Prior knowledge of perturbation data can significantly assist in inferring the relationship between chemical perturbations and their specific transcriptional response. However, current databases mostly contain cancer cell lines, which are unsuitable for the aforementioned inference in non-cancer cells. Here we present ChemPert (https://chempert.uni.lu/), a database consisting of 82270 transcriptional signatures across 167 non-cancer cell types, enabling more accurate predictions of perturbation responses and drugs compared to cancer databases in non-cancer cells. In particular, ChemPert correctly predicted drug effects for treating non-alcoholic steatohepatitis and novel drugs for osteoarthritis. Overall, ChemPert provides a valuable resource for drug discovery in non-cancer diseases.

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Section: Resultsmentioning

confidence: 99%

ChemPert: mapping between chemical perturbation and transcriptional response for non-cancer cells

Zheng

Okawa

Bravo

et al. 2022

Preprint

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“…Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a signaling protein of the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) family and the TNFR superfamily. TRAF6 inhibition has previously been demonstrated to decrease cytokines, attenuate immunological responses, and promote M.tb survival (32). It was observed that M.tb infection resulted in increased expression of TRAF6 in TCRb−/− as well as in wild-type mice but transfer of CD4+ T cells further significantly increased the mRNA expression of TRAF6 in TCRb −/− mice while no change was found in wild-type mice.…”

Section: Discussionmentioning

confidence: 98%

“…Tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase, is a signaling protein of the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) family and the TNFR superfamily (32). In this study, we also examined the mRNA expression of TRAF-6 in lung macrophages.…”

Section: Mrna Expression Of Inflammation Associated Markers In Lung Macrophagesmentioning

confidence: 99%

Macrophages Are the Key Players in Promoting Hyper-Inflammatory Response in a Mouse Model of TB-IRIS

et al. 2021

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TB-IRIS is an abnormal inflammatory response in a subset of HIV-TB co-infected patients shortly after initiation of anti-retroviral therapy (ART). Therapy in these patients could have greatly improved the life expectancy as ART reconstitutes the function and number of CD4+ T cells and many patients see improvement in symptoms but paradoxically up to 54% of co-infected patients develop TB-IRIS. Different studies have indicated that both innate and adaptive immunity are involved in the pathology of IRIS but the role of macrophages in abnormal activation of CD4+ T cells is poorly understood. Since macrophages are one of the major antigen-presenting cells and are infected by M.tb at a high frequency, they are very much likely to be involved in the development of TB-IRIS. In this study, we have developed a mouse model of experimental IRIS, in which M.tb-infected T-cell knockout mice undergo a fatal inflammatory disease after CD4+ T cell reconstitution. Lung macrophages and blood monocytes from M.tb-infected TCRβ−/− mice showed upregulated expression of cell surface activation markers and also showed higher mRNA expression of inflammation-associated chemokines and matrix metalloproteases responsible for tissue damage. Furthermore, cytokine and TLR signaling feedback mechanism to control excessive inflammation was also found to be dysregulated in these macrophages under lymphopenic conditions. Previous studies have shown that hyperactive CD4+ T cells are responsible for disease induction and our study shows that somehow macrophages are in a higher activated state when infected with M.tb in an immune-deficient condition, which results in excessive activation of the adoptively transferred CD4+ T cells. Understanding of the mechanisms underlying the pathophysiology of TB-IRIS would facilitate identification of prospective biomarkers for disease development in HIV-TB co-infected patients before starting antiretroviral therapy.

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“…The upregulation of autophagy leads to the resistance of cancer cells to various anticancer drugs [ 56 , 57 ]. Upon cellular stimuli including TLRs, IL-17R, and TNFR, TRAF6 regulates tumor cell proliferation, survival, apoptosis, and invasion through different signaling pathways [ 8 , 58 ]. As depicted in Fig.…”

Section: Discussionmentioning

confidence: 99%

USP15 negatively regulates lung cancer progression through the TRAF6-BECN1 signaling axis for autophagy induction

et al. 2022

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TNF receptor-associated factor 6 (TRAF6)-BECN1 signaling axis plays a pivotal role in autophagy induction through ubiquitination of BECN1, thereby inducing lung cancer migration and invasion in response to toll-like receptor 4 (TLR4) stimulation. Herein, we provide novel molecular and cellular mechanisms involved in the negative effect of ubiquitin-specific peptidase 15 (USP15) on lung cancer progression. Clinical data of the TCGA and primary non-small cell lung cancer (NSCLC) patients (n = 41) revealed that the expression of USP15 was significantly downregulated in lung cancer patients. Importantly, USP15-knockout (USP15KO) A549 and USP15KO H1299 lung cancer cells generated with CRISPR-Cas9 gene-editing technology showed increases in cancer migration and invasion with enhanced autophagy induction in response to TLR4 stimulation. In addition, biochemical studies revealed that USP15 interacted with BECN1, but not with TRAF6, and induced deubiquitination of BECN1, thereby attenuating autophagy induction. Notably, in primary NSCLC patients (n = 4) with low expression of USP15, 10 genes (CCNE1, MMP9, SFN, UBE2C, CCR2, FAM83A, ETV4, MYO7A, MMP11, and GSDMB) known to promote lung cancer progression were significantly upregulated, whereas 10 tumor suppressor genes (FMO2, ZBTB16, FCN3, TCF21, SFTPA1B, HPGD, SOSTDC1, TMEM100, GDF10, and WIF1) were downregulated, providing clinical relevance of the functional role of USP15 in lung cancer progression. Taken together, our data demonstrate that USP15 can negatively regulate the TRAF6-BECN1 signaling axis for autophagy induction. Thus, USP15 is implicated in lung cancer progression.

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Mechanism by which TRAF6 Participates in the Immune Regulation of Autoimmune Diseases and Cancer

Cited by 24 publications

References 141 publications

ChemPert: mapping between chemical perturbation and transcriptional response for non-cancer cells

ChemPert: mapping between chemical perturbation and transcriptional response for non-cancer cells

Macrophages Are the Key Players in Promoting Hyper-Inflammatory Response in a Mouse Model of TB-IRIS

USP15 negatively regulates lung cancer progression through the TRAF6-BECN1 signaling axis for autophagy induction

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