Neuronal RING finger protein 11 (RNF11) regulates canonical NF-κB signaling
| Autor: | Nirjari V. Dalal, Adam L. Orr, Jason J. Fritz, Ranjita Betarbet, Craig J. Heilman, Jeremy H. Herskowitz, Allan I. Levey, Leah A Roesch, Elaine L. Pranski, James J. Lah |
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| Rok vydání: | 2012 |
| Předmět: |
Immunoprecipitation
Immunology Biology lcsh:RC346-429 NF-κB Small hairpin RNA Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Neuroinflammation Cell Line Tumor medicine Animals Humans lcsh:Neurology. Diseases of the nervous system Cells Cultured E3 ligase 030304 developmental biology Neurons 0303 health sciences Messenger RNA Research General Neuroscience NF-kappa B Neuron NFKB1 Ubiquitin ligase DNA-Binding Proteins Mice Inbred C57BL A20 medicine.anatomical_structure Neurology Gene Knockdown Techniques biology.protein Signal transduction Carrier Proteins Neuroscience 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Journal of Neuroinflammation Journal of Neuroinflammation, Vol 9, Iss 1, p 67 (2012) |
| ISSN: | 1742-2094 |
| DOI: | 10.1186/1742-2094-9-67 |
| Popis: | Background The RING domain-containing protein RING finger protein 11 (RNF11) is a member of the A20 ubiquitin-editing protein complex and modulates peripheral NF-κB signaling. RNF11 is robustly expressed in neurons and colocalizes with a population of α-synuclein-positive Lewy bodies and neurites in Parkinson disease patients. The NF-κB pathway has an important role in the vertebrate nervous system, where the absence of NF-κB activity during development can result in learning and memory deficits, whereas chronic NF-κB activation is associated with persistent neuroinflammation. We examined the functional role of RNF11 with respect to canonical NF-κB signaling in neurons to gain understanding of the tight association of inflammatory pathways, including NF-κB, with the pathogenesis of neurodegenerative diseases. Methods and results Luciferase assays were employed to assess NF-κB activity under targeted short hairpin RNA (shRNA) knockdown of RNF11 in human neuroblastoma cells and murine primary neurons, which suggested that RNF11 acts as a negative regulator of canonical neuronal NF-κB signaling. These results were further supported by analyses of p65 translocation to the nucleus following depletion of RNF11. Coimmunoprecipitation experiments indicated that RNF11 associates with members of the A20 ubiquitin-editing protein complex in neurons. Site-directed mutagenesis of the myristoylation domain, which is necessary for endosomal targeting of RNF11, altered the impact of RNF11 on NF-κB signaling and abrogated RNF11’s association with the A20 ubiquitin-editing protein complex. A partial effect on canonical NF-κB signaling and an association with the A20 ubiquitin-editing protein complex was observed with mutagenesis of the PPxY motif, a proline-rich region involved in Nedd4-like protein interactions. Last, shRNA-mediated reduction of RNF11 in neurons and neuronal cell lines elevated levels of monocyte chemoattractant protein 1 and TNF-α mRNA and proteins, suggesting that NF-κB signaling and associated inflammatory responses are aberrantly regulated in the absence of RNF11. Conclusions Our findings support the hypothesis that, in the nervous system, RNF11 negatively regulates canonical NF-κB signaling. Reduced or functionally compromised RNF11 could influence NF-κB-associated neuronal functions, including exaggerated inflammatory responses that may have implications for neurodegenerative disease pathogenesis and progression. |
| Databáze: | OpenAIRE |
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