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

Journal of Neuroinflammation

Ranjita S Betarbet¹  Allan I Levey¹  James J Lah¹  Craig Heilman¹  Jason J Fritz¹  Leah A Roesch¹  Adam L Orr¹  Jeremy H Herskowitz¹  Nirjari V Dalal¹  Elaine L Pranski¹ 

[1] Center for Neurodegenerative Disease, Department of Neurology, Emory University School of Medicine, 615 Michael St., Suite 500, Atlanta, GA, 30322, USA

关键词: Neuron;    Neuroinflammation;    NF-κB;    E3 ligase;    A20;   

Others  :  1212684
DOI  :  10.1186/1742-2094-9-67

 received in 2011-11-01, accepted in 2012-04-16,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Pranski et al; licensee BioMed Central Ltd.

【 图 表 】

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