Leucine-rich repeat kinase 2 (LRRK2) stimulates IL-1β-mediated inflammatory signaling through phosphorylation of RCAN1

Kyung A. Han, Lang Yoo, Jee Y. Sung, Sun A. Chung, Ji W. Um, Hyeyoung Kim, Wongi Seol, Kwang C. Chung

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7 Citations (Scopus)

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.

Original languageEnglish
Article number125
JournalFrontiers in Cellular Neuroscience
Volume11
DOIs
Publication statusPublished - 2017 May 11

Bibliographical note

Funding Information:
This work was supported by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (2014M3C7A1064545 and 2015R1A2A2A01003080 to KCC), South Korea. This work was also supported in part by the Yonsei University Future-leading Research Initiative of 2015 (2015-22-0055 to KCC).

Publisher Copyright:
© 2017 Han, Yoo, Sung, Chung, Um, Kim, Seol and Chung.

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience

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