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

Song, Yinjing; Lai, Lihua; Chong, Zhenlu; He, Jia; Zhang, Yuanyuan; Xue, Yue; Xie, Yiwei; Chen, Songchang; Dong, Ping; Chen, Luoquan; Chen, Zhimin; Dai, Feng; Wan, Xiaopeng; Xiao, Peng; Cao, Xuetao; Liu, Yang; Wang, Qingqing

doi:10.1038/ncomms14654

Cited by 59 publications

(56 citation statements)

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“…RIG-I activity is significantly modulated through ubiquitylation processes mediated by several E3 ligases [34,[44][45][46][47], differentially expressed depending on the tumor context [48,49]. MEX3C, TRIM4 and TRIM25 are the most important E3 ligases for positive regulation of RIG-I activity in response to viral infection, whereas RNF122 and RNF125 have been described to mediate the ubiquitin-dependent degradation of this cytosolic innate immune receptor.…”

Section: Discussionmentioning

confidence: 99%

The RNA-Binding Ubiquitin Ligase MEX3A Affects Glioblastoma Tumorigenesis by Inducing Ubiquitylation and Degradation of RIG-I

Bufalieri

Caimano

Severini

et al. 2020

Cancers

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Glioblastoma multiforme (GB) is the most malignant primary brain tumor in humans, with an overall survival of approximatively 15 months. The molecular heterogeneity of GB, as well as its rapid progression, invasiveness and the occurrence of drug-resistant cancer stem cells, limits the efficacy of the current treatments. In order to develop an innovative therapeutic strategy, it is mandatory to identify and characterize new molecular players responsible for the GB malignant phenotype. In this study, the RNA-binding ubiquitin ligase MEX3A was selected from a gene expression analysis performed on publicly available datasets, to assess its biological and still-unknown activity in GB tumorigenesis. We find that MEX3A is strongly up-regulated in GB specimens, and this correlates with very low protein levels of RIG-I, a tumor suppressor involved in differentiation, apoptosis and innate immune response. We demonstrate that MEX3A binds RIG-I and induces its ubiquitylation and proteasome-dependent degradation. Further, the genetic depletion of MEX3A leads to an increase of RIG-I protein levels and results in the suppression of GB cell growth. Our findings unveil a novel molecular mechanism involved in GB tumorigenesis and suggest MEX3A and RIG-I as promising therapeutic targets in GB.Cancers 2020, 12, 321 2 of 16 treatments [2]. The current therapeutic protocol for GB patients consists of surgical resection of tumor mass and subsequent concomitant radiotherapy and chemotherapy. However, these approaches show very limited effectiveness, resulting in a high rate of relapse and subsequent deterioration of the patient's neurological and physiological status [2,5].In the recent years, several genetic and epigenetic aberrations in molecular pathways (i.e., WNT and Hedgehog signaling) [6-9] have been associated with GB onset and progression, representing potential therapeutic targets and biomarkers for early prognosis [2,3,5]. Hence, the identification and characterization of new molecular players involved in GB tumorigenesis is essential for developing more effective and innovative therapies against this aggressive malignancy.Ubiquitylation is a post-translational modification that controls a wide range of cellular functions (i.e., protein degradation, endocytosis and trafficking) and the most important physiological processes [10,11]. Ubiquitylation is mediated by an enzymatic cascade, in which the E3-ubiquitin ligases are the main players, responsible for the recognition of specific substrates and the final transferring of ubiquitin moieties onto target proteins.Deregulation or mutations of E3-ubiquitin ligases have been associated with several human tumors; for this reason, they are considered to be promising targets for novel anticancer therapies [12][13][14]. At present, very little information is available about the role of E3 ligases and ubiquitylation processes in GB development and progression [15][16][17].In this regard, we evaluated the expression levels of catalytic E3-ubiquitin ligase complex components [18] and F-b...

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Section: Discussionmentioning

confidence: 99%

The RNA-Binding Ubiquitin Ligase MEX3A Affects Glioblastoma Tumorigenesis by Inducing Ubiquitylation and Degradation of RIG-I

Bufalieri

Caimano

Severini

et al. 2020

Cancers

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“…HEK293T cells (American Type Culture Collection [ATCC], CRL-11268) were maintained in DMEM medium, and thioglycolate-elicited mouse peritoneal macrophages (BD, 3190383; Merck, 1.08191.0500) were cultured in RPMI 1640 medium with 10% (vol/vol) FCS. BMDMs were generated using BM from femurs and tibiae of 6-to 8-week-old mice (25).…”

Section: Discussionmentioning

confidence: 99%

“…FBXW7 is also reported to regulate lipid metabolism (22), target osteogenic and chondrogenic transcriptional factors (23), interact with parkin, and play important roles in Parkinson's disease (24). Our previous study showed that FBXW7 is critical for promoting innate antiviral immunity by mediating the ubiquitination of SHP2 (25). However, the function and mechanisms of FBXW7 in inflammation responses have not been clarified.…”

Section: Introductionmentioning

confidence: 99%

Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation

Song

et al. 2019

Journal of Clinical Investigation

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103

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2E) and F4/80 + macrophages (Figure 2F) after DSS treatment for 5 days compared with expression in the colons of healthy mice. These results suggest that increased FBXW7 expression in monocytes and macrophages was correlated with local colonic inflammation in both humans and mice. Fbxw7 deficiency attenuates experimental colitis. To investigate the role of Fbxw7 in macrophages in colitis, LysM-Cre + Fbxw7 fl/fl (LysM + Fbxw7 fl/fl) mice and their control littermates (Fbxw7 fl/fl) were subjected to acute colitis induction using 3% DSS. Colitisinduced macroscopic changes (body weight loss, diarrhea, and rectal bleeding) were significantly alleviated in the LysM + Fbxw7 fl/fl mice compared with Fbxw7 fl/fl littermates (Figure 3A). LysM + Fbxw7 fl/fl mice sacrificed on day 9 displayed significantly longer colons (Figure 3B), milder epithelial damage, and deceased areas of mucosal ulceration (Figure 3C and Supplemental Figure 2A) compared with Fbxw7 fl/fl littermates. Moreover, expression levels of the tight junction genes Cldn1, Cldn2, Ocln, and Tjp1 (Supplemental Figure 2B) and of TJP1 protein (Supplemental Figure 2C) were significantly higher in the epithelia of LysM + Fbxw7 fl/fl mice compared with Fbxw7 fl/fl littermates after DSS treatment, which indicated that the epithelial barrier integrity was less disrupted in mice with myeloid-specific Fbxw7 deficiency. At the same time, LysM + Fbxw7 fl/fl mice showed significantly improved survival rates compared with Fbxw7 fl/fl littermates after 4% DSS treatment (Figure 3D), indicating that Fbxw7 deficiency protects mice from DSS-induced colitis. During the recovery period of intestinal inflammation, the rate of body weight gain was more rapid in LysM + Fbxw7 fl/fl mice than in Fbxw7 fl/fl littermates (Figure 3E). Moreover, LysM + Fbxw7 fl/fl mice had longer colon lengths than did their Fbxw7 fl/fl littermates (Figure 3F) on day 15. Similarly, TNBS-induced colon shortening, the disease activity index (DAI), body weight loss, and epithelial damage were also alleviated in LysM + Fbxw7 fl/fl mice compared with Fbxw7 fl/fl littermates (Supplemental Figure 3, AD). These findings indicate that myeloid Fbxw7 deficiency attenuates experimental colitis. Fbxw7 deficiency decreases proinflammatory MPh accumulation. Microbiota-induced inflammation is critical for the regulation of intestinal homeostasis. To determine whether the decreased DSS colitis susceptibility in LysM + Fbxw7 fl/fl mice was mediated by shifts in gut microbiota, we analyzed the fecal microbiota composition in LysM + Fbxw7 fl/fl mice and Fbxw7 fl/fl littermates. The relative abundance of bacteria at the phylum level and the species composition cluster according to operational taxonomic units (OTUs) among LysM + Fbxw7 fl/fl mice and Fbxw7 fl/fl littermates are shown in Supplemental Figure 4A and Figure 4A, respectively. Moreover, microbial community diversity (Figure 4B) and microbial community composition (Supplemental Figure 4B) were not significantly different between LysM + Fbxw7 fl/fl mice and Fbxw7 fl/fl li...

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“…For immunoblot analysis, cells were lysed with cell lysis buffer (Cell Signaling Technology; 9803) supplemented with a protease inhibitor "cocktail" (Sigma; P8340). The antibodies for immunoblot analysis were used as we previously described (17).…”

Section: Immunoblot and Immunoprecipitation Analysismentioning

confidence: 99%

SOX9/FXYD3/Src Axis Is Critical for ER+ Breast Cancer Stem Cell Function

Xue

Lai

Lian

et al. 2019

Molecular Cancer Research

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The presence of cancer stem cells (CSC), which possess the ability of self-renewal and cancer initiation, is correlated with poor prognosis and drug resistance of breast cancer patients. But the molecular regulatory networks for maintenance of CSC function still remain unclear. Here, we identified that an estrogen-inducible gene , whose expression is significantly upregulated in ER breast CSCs, is a critical player for regulating ER breast CSC function. FXYD3 amplification is crucial in mediating tamoxifen resistance in ER breast cancer cells. Interestingly, we also find that stem cell-related transcription factor SOX9 directly promotes FXYD3 expression, and FXYD3 is indispensable for SOX9 nucleus localization, thus forming a positive regulatory feedback loop for FXYD3 amplification and function. In terms of mechanism, FXYD3 interacts with Src and ERα to form an activated complex and triggers Src to transduce nongenomic estrogen signaling for facilitating ER breast CSCs. Collectively, these results establish a critical role for SOX9/FXYD3/Src axis in boosting nongenomic estrogen signaling and SOX9 nucleus entry, which is required for maintenance of ER breast CSCs and endocrine resistance. Targeting FXYD3-mediated pathway might be a promising therapeutic strategy for hormone therapy-refractory ER breast cancer. SOX9/FXYD3/Src axis is critical for promoting CSC function and tamoxifen resistance in ER breast cancer.

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

Cited by 59 publications

References 50 publications

The RNA-Binding Ubiquitin Ligase MEX3A Affects Glioblastoma Tumorigenesis by Inducing Ubiquitylation and Degradation of RIG-I

The RNA-Binding Ubiquitin Ligase MEX3A Affects Glioblastoma Tumorigenesis by Inducing Ubiquitylation and Degradation of RIG-I

Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation

SOX9/FXYD3/Src Axis Is Critical for ER+ Breast Cancer Stem Cell Function

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