The E3 ubiquitin ligase RNF121 is a positive regulator of NF-κB activation

Zemirli, Naïma; Pourcelot, Marie; Dogan, Neslihan; Vázquez, Aimé; Arnoult, Damien

doi:10.1186/s12964-014-0072-8

Cited by 12 publications

(11 citation statements)

References 20 publications

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“…Previously identified negative (RNF125) and positive (RNF135, TRIM14) regulators of RIG-I mediated IFN-I transcription were found to suppress IFN-I signaling in our study262728. Similarly, RNF121, a previously reported positive regulator of innate immune receptor dependent NFkB activation, was found to attenuate IFN-I signaling upon overexpression in this study29. IFN-I signaling suppressor STUB1 was previously identified to promote TLR4 and TLR9 signaling30.…”

Section: Discussionsupporting

confidence: 73%

Global functional profiling of human ubiquitome identifies E3 ubiquitin ligase DCST1 as a novel negative regulator of Type-I interferon signaling

Nair

Bist

Dikshit

et al. 2016

Sci Rep

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Type I interferon (IFN-I) mediated innate immune response controls virus infections by inducing the expression of interferon stimulated genes (ISGs). Although ubiquitination plays key roles in immune signaling regulation, a human genome-wide understanding of the role of E3 ubiquitin ligases in interferon mediated ISG induction is lacking. Here, we report a genome-wide profiling of the effect of ectopic expression of 521 E3 ubiquitin ligases and substrate recognition subunits encoded in the human genome (which constitutes 84.4% of all ubiquitination related genes encoded in the human genome, hereafter termed Human Ubiquitome) on IFNβ mediated induction of interferon stimulated DNA response element (ISRE) driven reporter activity. We identified 96 and 42 genes of the human ubiquitome as novel negative and positive regulators of interferon signaling respectively. Furthermore, we characterized DCST1 as a novel E3 ubiquitin ligase negatively regulating interferon response. Ectopic expression and gene silencing of DCST1 respectively attenuated and increased ISRE reporter activity. DCST1 regulated Type I interferon signaling by interacting with and promoting ubiquitination-mediated degradation of STAT2, an essential component of antiviral gene induction. In summary, this study provided a systems level view on the role of human ubiquitination associated genes in Type I interferon response.

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Section: Discussionsupporting

confidence: 73%

Global functional profiling of human ubiquitome identifies E3 ubiquitin ligase DCST1 as a novel negative regulator of Type-I interferon signaling

Nair

Bist

Dikshit

et al. 2016

Sci Rep

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“…Consistent with the possible role of RNF121 in the UPR pathway, we also found that treatment of human cells with ER‐stress inducing agents such as tunicamycin, and oxidative stress inducing agent, hydrogen peroxide upregulates expression of RNF121 (Figure S6A,B). In agreement with its role in the regulation of cellular processes in C. elegans , a recent study also suggests that RNF121 controls distal tip cell migration and NF‐κB signaling . Consistent with our observation, while the current manuscript was in preparation, Ogino et al reported that RNF121 also regulates maturation of voltage‐gated sodium channel .…”

Section: Discussionsupporting

confidence: 91%

“…RNF121 was recently identified as an ER localized ubiquitin E3 ligase in C. elegans . However, its cellular expression and function in mammalian cells remains largely unknown.…”

Section: Resultsmentioning

confidence: 99%

RNF121 Inhibits Angiogenic Growth Factor Signaling by Restricting Cell Surface Expression of VEGFR‐2

Maghsoudlou

Meyer

Rezazadeh

et al. 2015

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Ligand stimulation promotes downregulation of RTKs, a mechanism by which RTKs, through the ubiquitination pathway are removed from the cell surface, causing a temporary termination of RTK signaling. The molecular mechanisms governing RTK trafficking and maturation in the endoplasmic reticulum (ER)/Golgi compartments are poorly understood. VEGFR-2 is a prototypic RTK that plays a critical role in physiologic and pathologic angiogenesis. Here we demonstrate that Ring Finger Protein 121 (RNF121), an endoplasmic reticulum ubiquitin E3 ligase, is expressed in endothelial cells and regulates maturation of VEGFR-2. RNF121 recognizes newly synthesized VEGFR-2 in the ER and controls its trafficking and maturation. Over-expression of RNF121 promoted ubiquitination of VEGFR-2, inhibited its maturation resulted a significantly reduced VEGFR-2 presence at the cell surface. Conversely, the shRNA-mediated knockdown of RNF121 in primary endothelial cells reduced VEGFR-2 ubiquitination and increased its cell surface level. The RING Finger domain of RNF121 is required for its activity toward VEGFR-2, as its deletion significantly reduced the effect of RNF121 on VEGFR-2. Additionally, RNF121 inhibited VEGF-induced endothelial cell proliferation and angiogenesis. Taken together, these data identify RNF121 as a key determinant of angiogenic signaling that restricts VEGFR-2 cell surface presence and its angiogenic signaling.

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“…MIB1-deficient cells have enhanced basal levels of IκBα compared with wild-type cells, 179 while the knockdown of RNF121 results in impaired IκBα degradation in response to a range of stimuli, including the ligation of TLRs, Nod-like receptors (NLRs), RIG-I-like receptors (RLRs), or after DNA damage. 180 βTrCP has been shown to mediate the ubiquitination of both IκBα 17 and IκBβ, 18 and a dominant negative form of the ligase prevents localization of NF-κB to the nucleus of human embryonic kidney (HEK) cells in response to TNFα stimulation. 17 Inhibition of these ligases in a targeted manner could result in reduced IκB degradation and consequently the diminished translocation of active NF-κB to the nucleus, regulating NF-κB-dependent gene transcription and the production of proinflammatory mediators.…”

Section: Dubs and E3 Ligasesmentioning

confidence: 99%

Modulation of NF-κB Signaling as a Therapeutic Target in Autoimmunity

2016

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Autoimmune diseases arise from the loss of tolerance to endogenous self-antigens, resulting in a heterogeneous range of chronic conditions that cause considerable morbidity and mortality worldwide. In Western countries, over 5% of the population is affected by some form of autoimmune disease, with enhanced or inappropriate activation of nuclear factor (NF)–κB implicated in a number of these conditions. Although treatment strategies for autoimmunity have improved significantly in recent years, current therapeutics are still not capable of achieving satisfactory disease management in all patients, and as such, the therapeutic modulation of NF-κB is an attractive target in autoimmunity. To date, no NF-κB inhibitors have progressed to the clinic for the treatment of autoimmunity, but a variety of promising approaches targeting multiple stages of the NF-κB pathway are currently being explored. This review focuses on the current strategies being investigated for the inhibition of the NF-κB pathway in autoimmune diseases and considers potential future strategies for the therapeutic targeting of this crucial transcription factor.

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The E3 ubiquitin ligase RNF121 is a positive regulator of NF-κB activation

Cited by 12 publications

References 20 publications

Global functional profiling of human ubiquitome identifies E3 ubiquitin ligase DCST1 as a novel negative regulator of Type-I interferon signaling

Global functional profiling of human ubiquitome identifies E3 ubiquitin ligase DCST1 as a novel negative regulator of Type-I interferon signaling

RNF121 Inhibits Angiogenic Growth Factor Signaling by Restricting Cell Surface Expression of VEGFR‐2

Modulation of NF-κB Signaling as a Therapeutic Target in Autoimmunity

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