Ubiquitin-specific protease 4 mitigates Toll-like/interleukin-1 receptor signaling and regulates innate immune activation
- Authors
- Zhou, F., Zhang, X., Dam, H.V., Dijke, P.T., Huang, H., and Zhang, L.
- ID
- ZDB-PUB-120125-31
- Date
- 2012
- Source
- The Journal of biological chemistry 287(14): 11002-11010 (Journal)
- Registered Authors
- Huang, Huizhe
- Keywords
- immunology, molecular cell biology, shRNA, ubiquitination, zebrafish, TRAF6, toll-like receptor/interleukin-1 receptor signaling, USP4, innate immune
- MeSH Terms
-
- Animals
- Cell Line
- DNA, Complementary/genetics
- Endopeptidases/genetics
- Endopeptidases/metabolism
- Humans
- Immunity, Innate*/drug effects
- Interleukin-1beta/pharmacology
- Lipopolysaccharides/pharmacology
- Mice
- NF-kappa B/metabolism
- Receptors, Interleukin-1/metabolism*
- Signal Transduction*/drug effects
- TNF Receptor-Associated Factor 6/metabolism
- Toll-Like Receptors/metabolism*
- Ubiquitin Thiolesterase/metabolism*
- Ubiquitination/drug effects
- PubMed
- 22262844 Full text @ J. Biol. Chem.
The Toll-like receptor (TLR)/interleukin 1 receptor (IL-1R) signaling pathway is essential for innate immune responses and immune homeostasis. Lysine 63 polyubiquitinated Tumor necrosis factor receptor-associated factor (TRAF)6 mediates its downstream signaling activation. In a gain of expression screen of 66 different deubiquitinating enzymes (DUBs), we identified ubiquitin-specific protease (USP)4 as a potent negative regulator of TLR/IL-1R signaling and TRAF6 interacting protein. USP4 deubiquitinates TRAF6 and thereby prevents the activation of NF-κB and AP-1 transcriptional factors and subsequent pro-inflammatory responses. LPS-treated usp4-depleted zebrafish larvaes expressed higher levels of pro-inflammatory cytokines and were more susceptible to endotoxic challenge. Taken together, our results demonstrate that USP4 plays an essential role in negative regulation of the TLR-IL-1R signaling-mediated innate immune response.