PINK1 positively regulates IL-1β-mediated signaling through Tollip and IRAK1 modulation

Background: parkinson disease (pd) is characterized by a slow,progressive degeneration of dopaminergic neurons in the substantianigra. the cause of neuronal loss in pd is not well understood,but several genetic loci,including pten-induced putative kinase 1 (pink1),have been linked to early-onset autosomal recessive forms of familial pd. neuroinflammation greatly contributes to pd neuronal degeneration and pathogenesis. il-1 is one of the principal cytokines that regulates various immune and inflammatory responses via the activation of the transcription factors nf-κb and activating protein-1. despite the close relationship between pd and neuroinflammation,the functional roles of pd-linked genes during inflammatory processes remain poorly understood.methods: to explore the functional roles of pink1 in response to il-1β stimulation,hek293 cells,mouse embryonic fibroblasts derived from pink1-null (pink1 -/-) and control (pink1 +/+) mice,and 293 il-1ri cells stably expressing type 1 il-1 receptor were used. immunoprecipitation and western blot analysis were performed to detect protein-protein interaction and protein ubiquitination. to confirm the effect of pink1 on nf-κb activation,nf-κb-dependent firefly luciferase reporter assay was conducted.results: pink1 specifically binds two components of the il-1-mediated signaling cascade,toll-interacting protein (tollip) and il-1 receptor-associated kinase 1 (irak1). the association of pink1 with tollip,a negative regulator of il-1β signaling,increases upon il-1β stimulation,which then facilitates the dissociation of tollip from irak1 as well as the assembly of the irak1-tnf receptor-associated factor 6 (traf6) complex. pink1 also enhances lys63-linked polyubiquitination of irak1,an essential modification of recruitment of nf-κb essential modulator and subsequent iκb kinase activation,and increases formation of the intermediate signalosome including irak1,traf6,and transforming growth factor-β activated kinase 1. furthermore,pink1 stimulates il-1β-induced nf-κb activity via suppression of tollip inhibitory action.conclusions: these results suggest that pink1 upregulates il-1β-mediated signaling through the functional modulation of tollip and irak1. these results further suggest that pink1 stimulates the ubiquitination of proximal molecules and increases signalosome formation in the il-1β-mediated signaling pathway. the present study therefore supports the idea of the close relationship between neuroinflammation and pd. © 2012 lee and chung; licensee biomed central ltd.