Neuronal RING finger protein 11 (RNF11) regulates canonical NF-κB signaling

Pranski, Elaine L.; Dalal, Nirjari V.; Herskowitz, Jeremy H.; Orr, Adam L.; Roesch, Leah A; Fritz, Jason J.; Heilman, Craig J.; Lah, James J.; Levey, Aĺlan I.; Betarbet, Ranjita

doi:10.1186/1742-2094-9-67

Cited by 17 publications

(40 citation statements)

References 81 publications

(112 reference statements)

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“…Cells were cultured in Dulbecco’s modified Eagle’s medium supplemented with L-glutamine (Lonza), inactivated fetal bovine serum (Lonza), and 1% penicillin/streptomycin (Bio Whittaker). Primary microglia cultures were prepared and harvested as described in [23]. All cultures were maintained at 37°C in 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…The constructs used for knockdown of RNF11 and overexpression of RNF11 have been previously described [23]. Lentiviruses were produced by the Emory University Viral Vector Core facility.…”

Section: Methodsmentioning

confidence: 99%

“…Immunoprecipitations (IPs) were performed as described in [23], using antibody against rabbit RNF11 (polyclonal antibody) described in [18]. Controls IPs were performed with beads alone to demonstrate specificity.…”

Section: Methodsmentioning

confidence: 99%

“…Quantitative Real-time PCR (qRT-PCR) was performed, as described previously [23], on a 7500 Fast RT-PCR instrument (Applied Biosystems) using TaqMan PCR master mix (Applied Biosystems) and gene-specific TaqMan probes (Applied Biosystems) against RNF11 (Mm00450014_m1), TNF-α (Mm00443258_m1), A20 (Mm00437121_m1), MCP-1 (Mm00441242_m1), IL1-B (Mm99999061_m1), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (Applied Biosystems). RNA samples were run in triplicate.…”

Section: Methodsmentioning

confidence: 99%

“…Additionally, RNF11enhances TGF-β and EGFR endosomal signalling by interacting with Smad4 and Smurf2 [22]. Moreover, RNF11 is an essential component of the A20 ubiquitin editing complex and negatively regulates NF-κB signalling, as demonstrated in a monocytic cell line [20] and neurons [23]. In the current study, we investigated the association of RNF11 with the A20 ubiquitin-editing complex in microglia, the immune cells and mediators of neuroinflammation in the CNS, and determined its role in the NF-κB signalling pathway, inflammatory response and cell survival.…”

Section: Introductionmentioning

confidence: 99%

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RNF11 modulates microglia activation through NF-κB signalling cascade

Dalal

Pranski

Tansey

et al. 2012

Neuroscience Letters

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Microglia are resident macrophages in the central nervous system (CNS) that play a major role in neuroinflammation and pathogenesis of several neurodegenerative diseases. Upon activation, microglia releases a multitude of pro-inflammatory factors that initiate and sustain an inflammatory response by activating various signalling pathways, including the NF-κB pathway in a feed forward cycle. In microglial cells, activation of NF-κB signalling is normally transient, while sustained NF-κB activation is associated with persistent neuroinflammation. RING finger protein 11 (RNF11), in association with A20 ubiquitin-editing complex, is one of the key negative regulators of NF-κB signalling pathway in neurons. In this study, we have demonstrated and confirmed this role of RNF11 in microglia, the immune cells of the CNS. Coimmunoprecipitation experiments showed that RNF11 and A20 interact in a microglial cell line, suggesting the presence of A20 ubiquitin-editing protein complex in microglial cells. Next, using targeted short hairpin RNA (shRNA) knockdown and over-expression of RNF11, we established that RNF11 expression levels are inversely related to NF-κB activation, as evident from altered expression of NF-κB transcribed genes. Moreover our studies, illustrated that RNF11 confers protection against LPS-induced cell cytotoxicity. Thus our investigations clearly demonstrated that microglial RNF11 is a negative regulator of NF-κB signalling pathway and could be a strong potential target for modulating inflammatory responses in neurodegenerative diseases.

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Section: Methodsmentioning

confidence: 99%

“…The constructs used for knockdown of RNF11 and overexpression of RNF11 have been previously described [23]. Lentiviruses were produced by the Emory University Viral Vector Core facility.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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RNF11 modulates microglia activation through NF-κB signalling cascade

Dalal

Pranski

Tansey

et al. 2012

Neuroscience Letters

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The RING domain of RING Finger 11 (RNF11) protein binds Ubc13 and inhibits formation of polyubiquitin chains

et al. 2018

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The Really Interesting New Gene (RING) Finger protein 11 (RNF11) is a subunit of the A20 ubiquitin-editing complex that ensures the transient nature of inflammatory responses. Although the role of RNF11 as a negative regulator of NF-κB signalling is well-documented, the molecular mechanisms that underpin this function are poorly understood. Here, we show that RNF11 binds both Ubc13 and the Ubc13~ubiquitin conjugate tightly and with similar affinity, but has minimal E3 ligase activity. Remarkably, RNF11 appears to bind Ubc13 so tightly that it outcompetes the E1 and an active E3 ligase. As a consequence, RNF11 may regulate the activity of E3s that rely on Ubc13 for ubiquitin chain assembly by limiting the availability of Ubc13 and its conjugate.

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RING finger protein 11 (RNF11) modulates susceptibility to 6-OHDA-induced nigral degeneration and behavioral deficits through NF-κB signaling in dopaminergic cells

Pranski

Dalal

Sanford

et al. 2013

Neurobiology of Disease

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Chronic activation of the NF-κB pathway is associated with progressive neurodegeneration in Parkinson’s disease (PD). Given the role of neuronal RING finger protein 11 (RNF11) as a negative regulator of the NF-κB pathway, in this report we investigated the function of RNF11 in dopaminergic cells in PD-associated neurodegeneration. We found that RNF11 knock-down in an in vitro model of PD mediated protection against 6-OHDA-induced toxicity. In converse, over-expression of RNF11 enhanced 6-OHDA-induced dopaminergic cell death. Furthermore, by directly manipulating NF-κB signaling, we showed that the observed RNF11-enhanced 6-OHDA toxicity is mediated through inhibition of NF-κB-dependent transcription of TNF-α, antioxidants GSS and SOD1, and anti-apoptotic factor BCL2. Experiments in an in vivo 6-OHDA rat model of PD recapitulated the in vitro results. In vivo targeted RNF11 over-expression in nigral neurons enhanced 6-OHDA toxicity, as evident by increased amphetamine-induced rotations and loss of nigral dopaminergic neurons as compared to controls. This enhanced toxicity was coupled with down-regulation of NF-κB transcribed GSS, SOD1, BCL2, and neurotrophic factor BDNF mRNA levels, in addition to decreased TNF-α mRNA levels in ventral mesenchephalon samples. In converse, knockdown of RNF11 was associated with protective phenotypes and increased expression of above-mentioned NF-κB transcribed genes. Collectively, our in vitro and in vivo data suggest that RNF11-mediated inhibition of NF-κB in dopaminergic cells exaggerates 6-OHDA toxicity by inhibiting neuroprotective responses while loss of RNF11 inhibition on NF-κB activity promotes neuronal survival. The decreased expression of RNF11 in surviving cortical and nigral tissue detected in PD patients, thus implies a compensatory response in the diseased brain to PD-associated insults. In summary, our findings demonstrate that RNF11 in neurons can modulate susceptibility to 6-OHDA toxicity through NF-κB mediated responses. This neuron-specific role of RNF11 in the brain has important implications for targeted therapeutics aimed at preventing neurodegeneration.

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Neuronal RING finger protein 11 (RNF11) regulates canonical NF-κB signaling

Cited by 17 publications

References 81 publications

RNF11 modulates microglia activation through NF-κB signalling cascade

RNF11 modulates microglia activation through NF-κB signalling cascade

The RING domain of RING Finger 11 (RNF11) protein binds Ubc13 and inhibits formation of polyubiquitin chains

RING finger protein 11 (RNF11) modulates susceptibility to 6-OHDA-induced nigral degeneration and behavioral deficits through NF-κB signaling in dopaminergic cells

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