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Ubiquitin-specific protease 4 mitigates Toll-like/interleukin-1 receptor signaling and regulates innate immune activation.

ABSTRACT: The Toll-like receptor (TLR)/IL-1 receptor (IL-1R) signaling pathway is essential for innate immune responses and immune homeostasis. Lys-63-polyubiquitinated TRAF6 mediates its downstream signaling activation. In a gain-of-expression screen of 66 different deubiquitinating enzymes, we identified USP4 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 transcription factors and subsequent proinflammatory responses. LPS-treated usp4-depleted zebrafish larvae expressed higher levels of proinflammatory 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.

SUBMITTER: Zhou F

PROVIDER: S-EPMC3322833 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Ubiquitin-specific protease 4 mitigates Toll-like/interleukin-1 receptor signaling and regulates innate immune activation.

Zhou FangFang F Zhang Xiaofei X van Dam Hans H Ten Dijke Peter P Huang Huizhe H Zhang Long L

The Journal of biological chemistry 20120119 14

The Toll-like receptor (TLR)/IL-1 receptor (IL-1R) signaling pathway is essential for innate immune responses and immune homeostasis. Lys-63-polyubiquitinated TRAF6 mediates its downstream signaling activation. In a gain-of-expression screen of 66 different deubiquitinating enzymes, we identified USP4 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 transcription factors and subse ...[more]

PMID: 22262844

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Project description:Developing biomaterials to control the responsiveness of innate immune cells represents a clinically relevant approach to treat diseases with an underlying inflammatory basis, such as sepsis. Sepsis can involve activation of Toll-like receptor (TLR) signaling, which activates numerous inflammatory pathways. The breadth of this inflammation has limited the efficacy of pharmacological interventions that target a single molecular pathway. Here, we developed cargo-less particles as a single-agent, multi-target platform to elicit broad anti-inflammatory action against innate immune cells challenged by multiple TLR agonists. The particles, prepared from poly(lactic-co-glycolic acid) (PLGA) and poly(lactic acid) (PLA), displayed potent molecular weight-, polymer composition-, and charge-dependent immunomodulatory properties, including downregulation of TLR-induced costimulatory molecule expression and cytokine secretion. Particles prepared using the anionic surfactant poly(ethylene-alt-maleic acid) (PEMA) significantly blunted the responses of antigen presenting cells to TLR4 (lipopolysaccharide) and TLR9 (CpG-ODN) agonists, demonstrating broad inhibitory activity to both extracellular and intracellular TLR ligands. Interestingly, particles prepared using poly(vinyl alcohol) (PVA), a neutrally-charged surfactant, only marginally inhibited inflammatory cytokine secretions. The biochemical pathways modulated by particles were investigated using TRanscriptional Activity CEll aRrays (TRACER), which implicated IRF1, STAT1, and AP-1 in the mechanism of action for PLA-PEMA particles. Using an LPS-induced endotoxemia mouse model, administration of PLA-PEMA particles prior to or following a lethal challenge resulted in significantly improved mean survival. Cargo-less particles affect multiple biological pathways involved in the development of inflammatory responses by innate immune cells and represent a potentially promising therapeutic strategy to treat severe inflammation.

Dataset Information

Ubiquitin-specific protease 4 mitigates Toll-like/interleukin-1 receptor signaling and regulates innate immune activation.

Publications

Ubiquitin-specific protease 4 mitigates Toll-like/interleukin-1 receptor signaling and regulates innate immune activation.

Similar Datasets

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