Inhibition of IRAK1 ubiquitination determines glucocorticoid sensitivity for tlr9-induced inflammation in macrophages

Fansheng Kong, Zhiwei Liu, Viral G. Jain, Kenjiro Shima, Takuji Suzuki, Louis J. Muglia, Daniel T. Starczynowski, Chandrashekhar Pasare, Sandip Bhattacharyya

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3654-3667
Number of pages14
JournalJournal of Immunology
Volume199
Issue number10
DOIs
StatePublished - Nov 15 2017

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Kong, F., Liu, Z., Jain, V. G., Shima, K., Suzuki, T., Muglia, L. J., Starczynowski, D. T., Pasare, C., & Bhattacharyya, S. (2017). Inhibition of IRAK1 ubiquitination determines glucocorticoid sensitivity for tlr9-induced inflammation in macrophages. Journal of Immunology, 199(10), 3654-3667. https://doi.org/10.4049/jimmunol.1700443