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

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. © 2012 pranski et al; licensee biomed central ltd.