title: PINK1 positively regulates IL-1β-mediated signaling through Tollip and IRAK1 modulation.
abstract: 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.
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Yonsei-ro 50, Seodaemun-gu, Seoul, 120-749, Korea.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Kwang Chul
authors.initials: KC
authors.lastname: Chung
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D047468:Immunoprecipitation; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology* / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011494:Protein Kinases / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014162:Transfection; D054875:Ubiquitination / Q000187:drug effects; D000099202:PTEN-Induced Putative Kinase
chemical_list: D053592:Interleukin-1 Receptor-Associated Kinases; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D008239:Lysine; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C485837:Tollip protein, mouse; C507768:IRAK1 protein, human