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

Hyun Jung Lee, Kwang Chul Chung

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Article number271
JournalJournal of Neuroinflammation
Volume9
DOIs
Publication statusPublished - 2012 Dec 17

Fingerprint

Interleukin-1 Receptor-Associated Kinases
Interleukin-1
Parkinson Disease
Proteins
TNF Receptor-Associated Factor 6
Ubiquitination
PTEN-induced putative kinase
Phosphotransferases
Activating Transcription Factors
Firefly Luciferases
Genetic Loci
Interleukin-1 Receptors
HEK293 Cells
Dopaminergic Neurons
Parkinsonian Disorders
Transforming Growth Factors
Immunoprecipitation

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

@article{172424cb262b4103b11a6729af529ed3,
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.",
author = "Lee, {Hyun Jung} and Chung, {Kwang Chul}",
year = "2012",
month = "12",
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doi = "10.1186/1742-2094-9-271",
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journal = "Journal of Neuroinflammation",
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PINK1 positively regulates IL-1β-mediated signaling through Tollip and IRAK1 modulation. / Lee, Hyun Jung; Chung, Kwang Chul.

In: Journal of Neuroinflammation, Vol. 9, 271, 17.12.2012.

Research output: Contribution to journalArticle

TY - JOUR

T1 - PINK1 positively regulates IL-1β-mediated signaling through Tollip and IRAK1 modulation

AU - Lee, Hyun Jung

AU - Chung, Kwang Chul

PY - 2012/12/17

Y1 - 2012/12/17

N2 - 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.

AB - 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.

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