TY - JOUR
T1 - Inhibition of IRAK1 ubiquitination determines glucocorticoid sensitivity for tlr9-induced inflammation in macrophages
AU - Kong, Fansheng
AU - Liu, Zhiwei
AU - Jain, Viral G.
AU - Shima, Kenjiro
AU - Suzuki, Takuji
AU - Muglia, Louis J.
AU - Starczynowski, Daniel T.
AU - Pasare, Chandrashekhar
AU - Bhattacharyya, Sandip
N1 - Funding Information:
This work was supported by the Center for Prevention of Preterm Birth, Cincinnati Children’s Hospital Medical Center.
Publisher Copyright:
Copyright © 2017 by The American Association of Immunologists, Inc.
PY - 2017/11/15
Y1 - 2017/11/15
N2 - Inflammatory responses are controlled by signaling mediators that are regulated by various posttranslational modifications. Recently, transcription-independent functions for glucocorticoids (GC) in restraining inflammation have emerged, but the underlying mechanisms are unknown. In this study, we report that GC receptor (GR)-mediated actions of GC acutely suppress TLR9-induced inflammation via inhibition of IL-1R-associated kinase 1 (IRAK1) ubiquitination. b-TrCP-IRAK1 interaction is required for K48-linked ubiquitination of IRAK1 at Lys134 and subsequent membrane-to-cytoplasm trafficking of IRAK1 interacting partners TNFR-associated factor 6 and TAK1 that facilitates NF-kB and MAPK activation. Upon costimulation of macrophages with GC and TLR9-engaging ligand, GR physically interacts with IRAK1 and interferes with protein-protein interactions between b-TrCP and IRAK1. Ablation of GR in macrophages prevents GC-dependent suppression of b-TrCP-IRAK1 interactions. This GCmediated suppression of IRAK1 activation is unique to TLR9, as GC treatment impairs TLR9 but not TLR4 ligand-induced K48- linked IRAK1 ubiquitination and trafficking of IRAK1 interacting partners. Furthermore, mutations in IRAK1 at Lys134 prevent TLR9 ligand-induced activation of inflammatory signaling mediators and synthesis of proinflammatory cytokines to an extent comparable to GC-mediated inhibition. Collectively, these findings identify a transcription-independent, rapid, and nongenomic GC suppression of TLR9 ligand-mediated IRAK1 ubiquitination as a novel mechanism for restraining acute inflammatory reactions.
AB - Inflammatory responses are controlled by signaling mediators that are regulated by various posttranslational modifications. Recently, transcription-independent functions for glucocorticoids (GC) in restraining inflammation have emerged, but the underlying mechanisms are unknown. In this study, we report that GC receptor (GR)-mediated actions of GC acutely suppress TLR9-induced inflammation via inhibition of IL-1R-associated kinase 1 (IRAK1) ubiquitination. b-TrCP-IRAK1 interaction is required for K48-linked ubiquitination of IRAK1 at Lys134 and subsequent membrane-to-cytoplasm trafficking of IRAK1 interacting partners TNFR-associated factor 6 and TAK1 that facilitates NF-kB and MAPK activation. Upon costimulation of macrophages with GC and TLR9-engaging ligand, GR physically interacts with IRAK1 and interferes with protein-protein interactions between b-TrCP and IRAK1. Ablation of GR in macrophages prevents GC-dependent suppression of b-TrCP-IRAK1 interactions. This GCmediated suppression of IRAK1 activation is unique to TLR9, as GC treatment impairs TLR9 but not TLR4 ligand-induced K48- linked IRAK1 ubiquitination and trafficking of IRAK1 interacting partners. Furthermore, mutations in IRAK1 at Lys134 prevent TLR9 ligand-induced activation of inflammatory signaling mediators and synthesis of proinflammatory cytokines to an extent comparable to GC-mediated inhibition. Collectively, these findings identify a transcription-independent, rapid, and nongenomic GC suppression of TLR9 ligand-mediated IRAK1 ubiquitination as a novel mechanism for restraining acute inflammatory reactions.
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U2 - 10.4049/jimmunol.1700443
DO - 10.4049/jimmunol.1700443
M3 - Article
C2 - 29038250
AN - SCOPUS:85033360286
SN - 0022-1767
VL - 199
SP - 3654
EP - 3667
JO - Journal of Immunology
JF - Journal of Immunology
IS - 10
ER -