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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

Title
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
Author
배옥남
Keywords
Innate immunity; Anti-viral signaling; Src-family-tyrosine kinases; IRF3; Type I interferon
Issue Date
2015-03
Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
Citation
CYTOKINE, v. 72, No. 1, Page. 63-70
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.
URI
http://www.sciencedirect.com/science/article/pii/S104346661400622Xhttp://repository.hanyang.ac.kr/handle/20.500.11754/100620
ISSN
1043-4666
DOI
10.1016/j.cyto.2014.12.008.
Appears in Collections:
COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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