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Leucine-Rich Repeat Kinase 2 (LRRK2) Stimulates IL-1 beta-Mediated Inflammatory Signaling through Phosphorylation of RCAN1

Title
Leucine-Rich Repeat Kinase 2 (LRRK2) Stimulates IL-1 beta-Mediated Inflammatory Signaling through Phosphorylation of RCAN1
Authors
Han, Kyung A.Yoo, LangSung, Jee Y.Chung, Sun A.Um, Ji W.Kim, HyeyoungSeol, WongiChung, Kwang C.
DGIST Authors
Um, Ji W.
Issue Date
2017-05-11
Citation
Frontiers in Cellular Neuroscience, 11
Type
Article
Article Type
Article
Keywords
ActivationAlzheimer&aposs Disease (AD)Calcineurin ActivityCerebrospinal FluidDown SyndromeInterleukin 1 BetaInterleukin 1 BetaLRRK2Lys63 Linked PolyubiquitinationNF Kappa BNF Kappa BNF Kappa BParkinson&aposs DiseaseParkinson&aposs DiseaseParkinson&aposs DiseasePhosphorylationPhosphorylationRCAN1ReceptorSyndrome Critical Region
ISSN
1662-5102
Abstract
Leucine-rich repeat kinase 2 (LRRK2) is a Ser/Thr kinase having mixed lineage kinase-like and GTPase domains, controlling neurite outgrowth and neuronal cell death. Evidence suggests that LRRK2 is involved in innate immune response signaling, but the underlying mechanism is yet unknown. A novel protein inhibitor of phosphatase 3B, RCAN1, is known to positively regulate inflammatory signaling through modulation of several intracellular targets of interleukins in immune cells. In the present study, we report that LRRK2 phosphorylates RCAN1 (RCAN1-1S) and is markedly up-regulated during interleukin-1β (IL-1β) treatment. During IL-1β treatment, LRRK2-mediated phosphorylation of RCAN1 promoted the formation of protein complexes, including that between Tollip and RCAN1. LRRK2 decreased binding between Tollip and IRAK1, which was accompanied by increased formation of the IRAK1-TRAF6 complex. TAK1 activity was significantly enhanced by LRRK2. Furthermore, LRRK2 enhanced transcriptional activity of NF-κB and cytokine IL-8 production. These findings suggest that LRRK2 might be important in positively modulating IL-1β-mediated signaling through selective phosphorylation of RCAN1. © 2017 Han, Yoo, Sung, Chung, Um, Kim, Seol and Chung.
URI
http://hdl.handle.net/20.500.11750/4178
DOI
10.3389/fncel.2017.00125
Publisher
Frontiers Research Foundation
Related Researcher
  • Author Um, Ji Won Um Laboratory
  • Research Interests Molecular and cellular mechanisms underlying synapse elimination; Key synaptic mechanisms associated with Alzheimer's disease and autism spectrum disorders; Synaptic homeostasis
Files:
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Collection:
Brain and Cognitive SciencesETC1. Journal Articles


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