Signal regulatory protein alpha negatively regulates both TLR3 and cytoplasmic pathways in type I interferon induction.
Recognition of double-stranded RNA (dsRNA) activates interferon-regulatory factor 3 (IRF3)-dependent expression of anti-viral factors. The innate immune system recognizes viral dsRNA through two distinct pathways. First, the Toll-like receptor 3 (TLR3) detects dsRNA phagocytosed in endosomes. In addition, the helicases retinoic acid induced protein I (RIG-I)/melanoma differentiation associated gene 5 (MDA5) binds cytoplasmic dsRNA generated during viral replication. Both RIG-I/MDA5 and TLR3 can bind polyriboinosinic:polyribocytidylic acid (poly(I:C)), the synthetic analog of viral dsRNA, and mediate type I IFN production. Here we show that signal regulatory protein (SIRP) alpha negatively regulates both TLR3- and RIG-1/MDA5-dependent anti-viral pathways. Suppression of SIRPalpha expression by RNA interference results in enhanced activation of IRF3 and MAPK pathways after poly(I:C) treatment, coupled with the up-regulation of IFN-beta and IFN-beta-inducible gene transcriptional activation. The requirement of phosphoinositide 3-kinase (PI3K) activity for the induction of IFN-beta and IFN-beta-inducible genes by dsRNA is supported by the observation that a PI3K inhibitor failed to activate IFN-beta and IFN-beta-inducible gene expression. PI3K, whose activity is essential for activation of IRF3, is recruited to the phosphorylated tyrosine residues of SIRPalpha upon poly(I:C) stimulation, which lead to a reduction in the activity of the downstream kinase AKT. Thus SIRPalpha may accomplish its inhibitory function in type I IFN induction, in part, through its association and sequestration of the signal transducer PI3K.
Dong
Li-Wei
LW
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, 225 Changhai Road, 200438 Shanghai, PR China.
Kong
Xiao-Ni
XN
Yan
He-Xin
HX
Yu
Le-Xing
LX
Chen
Lei
L
Yang
Wen
W
Liu
Qiong
Q
Huang
Dan-Dan
DD
Wu
Meng-Chao
MC
Wang
Hong-Yang
HY
D020816:Amino Acid Motifs; D000818:Animals; D000943:Antigens, Differentiation / Q000737:chemistry / Q000276:immunology*; D002460:Cell Line; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000737:chemistry / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology*; D015533:Transcriptional Activation / Q000187:drug effects
D000943:Antigens, Differentiation; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; C501922:Sirpa protein, mouse; D012330:RNA, Double-Stranded; D011971:Receptors, Immunologic; D050794:STAT1 Transcription Factor; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D019869:Phosphatidylinositol 3-Kinases; D011070:Poly I-C