A Src-family-tyrosine kinase, Lyn, is required for efficient IFN-beta, expression in pattern recognition receptor, RIG-I, signal pathway by interacting with IPS-1
- Authors
- Lim, Young Ju; Koo, Jung Bun; Hong, Eun-Hee; Park, Zee-Yong; Lim, Kyung-Min; Bae, Ok-Nam; Lee, Joo Young
- Issue Date
- Mar-2015
- Publisher
- ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
- Keywords
- Innate immunity; Anti-viral signaling; Src-family-tyrosine kinases; IRF3; Type I interferon
- Citation
- CYTOKINE, v.72, no.1, pp.63 - 70
- Indexed
- SCIE
SCOPUS
- Journal Title
- CYTOKINE
- Volume
- 72
- Number
- 1
- Start Page
- 63
- End Page
- 70
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/18820
- DOI
- 10.1016/j.cyto.2014.12.008
- ISSN
- 1043-4666
- Abstract
- Retinoic acid-inducible gene I (RIG-I) plays an important role in antiviral immunity as a cytosolic receptor recognizing invading viruses. The activation of downstream signaling pathways led by IFN-beta promoter stimulator-1 (IPS-1), an adaptor, is known to culminate in the activation of IRFs and the expression of type I interferons. However, the role of Src-family-tyrosine kinases (STKs) in the RIG-I signaling pathway has not been fully evaluated. Through a combined approach of immunoprecipitation and micro reversed phase liquid chromatography-tandem mass spectrometry (RPLC-MS/MS) analysis, we established that Lyn, one of the STKs, is associated with RIG-I in macrophages. The association of Lyn and RIG-I was confirmed by co-immunoprecipitation study with 293T cells overexpressing Lyn and RIG-I. Suppression of Lyn by siRNA knockdown or a pharmacological inhibitor (PP2) resulted in the attenuation of IRF3 activation and IFN-beta expression induced by short poly I:C, a RIG-I agonist, in macrophages. Lyn activation, as determined by phosphorylation of Tyr396 residue, was observed upon short poly I:C stimulation in the mitochondria of macrophages. Short poly I:C induced the formation of speckle-like aggregates of Lyn, which are prominent in mitochondria. Lyn associated with IPS-1, an adaptor protein of RIG-I, which resides on mitochondria membrane. Helicase domain of RIG-I and CARD of IPS-1 are responsible for the interaction with Lyn while SH3 and SH2 domains in Lyn are required for the association with RIG-I and IPS-1. Collectively, our results indicate that Lyn plays a positive regulatory role in RIG-I-mediated interferon expression as a downstream component of IPS-1. They provide further information as to how tyrosine kinases such as STKs play a role in the regulation of antiviral immunity. (C) 2014 Elsevier Ltd. All rights reserved.
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