Annexin-A1 regulates TLR-mediated IFN-β production through an interaction with TANK-binding kinase 1.
TLRs play a pivotal role in the recognition of bacteria and viruses. Members of the family recognize specific pathogen sequences to trigger both MyD88 and TRIF-dependent pathways to stimulate a plethora of cells. Aberrant activation of these pathways is known to play a critical role in the development of autoimmunity and cancer. However, how these pathways are entirely regulated is not fully understood. In these studies, we have identified Annexin-A1 (ANXA1) as a novel regulator of TLR-induced IFN-β and CXCL10 production. We demonstrate that in the absence of ANXA1, mice produce significantly less IFN-β and CXCL10, and macrophages and plasmacytoid dendritic cells have a deficiency in activation following polyinosinic:polycytidylic acid administration in vivo. Furthermore, a deficiency in activation is observed in macrophages after LPS and polyinosinic:polycytidylic acid in vitro. In keeping with these findings, overexpression of ANXA1 resulted in enhanced IFN-β and IFN-stimulated responsive element promoter activity, whereas silencing of ANXA1 impaired TLR3- and TLR4-induced IFN-β and IFN-stimulated responsive element activation. In addition, we show that the C terminus of ANXA1 directly associates with TANK-binding kinase 1 to regulate IFN regulatory factor 3 translocation and phosphorylation. Our findings demonstrate that ANXA1 plays an important role in TLR activation, leading to an augmentation in the type 1 IFN antiviral cytokine response.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456;
Pradeep
P
Bist
Shinla
S
Shu
Huiyin
H
Lee
Suruchi
S
Arora
Sunitha
S
Nair
Jyue Yuen
JY
Lim
Jivanaah
J
Dayalan
Stephan
S
Gasser
Subhra K
SK
Biswas
Anna-Marie
AM
Fairhurst
Lina H K
LH
Lim
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017305:Annexin A1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000096:biosynthesis; D003713:Dendritic Cells / Q000378:metabolism; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis*; D008070:Lipopolysaccharides; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010766:Phosphorylation; D011070:Poly I-C / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D017305:Annexin A1; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; C573274:annexin A1, mouse; D016899:Interferon-beta; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D011070:Poly I-C