Disabled-2 is a negative immune regulator of lipopolysaccharide-stimulated Toll-like receptor 4 internalization and signaling

Wei Shan Hung, Pin Ling, Ju Chien Cheng, Shy Shin Chang, Ching Ping Tseng

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Toll-like receptor 4 (TLR4) plays a pivotal role in the host response to lipopolysaccharide (LPS), a major cell wall component of Gram-negative bacteria. Here, we elucidated whether the endocytic adaptor protein Disabled-2 (Dab2), which is abundantly expressed in macrophages, plays a role in LPS-stimulated TLR4 signaling and trafficking. Molecular analysis and transcriptome profiling of RAW264.7 macrophage-like cells expressing short-hairpin RNA of Dab2 revealed that Dab2 regulated the TLR4/TRIF pathway upon LPS stimulation. Knockdown of Dab2 augmented TRIF-dependent interferon regulatory factor 3 activation and the expression of subsets of inflammatory cytokines and interferon-inducible genes. Dab2 acted as a clathrin sponge and sequestered clathrin from TLR4 in the resting stage of macrophages. Upon LPS stimulation, clathrin was released from Dab2 to facilitate endocytosis of TLR4 for triggering the TRIF-mediated pathway. Dab2 functions as a negative immune regulator of TLR4 endocytosis and signaling, supporting a novel role for a Dab2-associated regulatory circuit in controlling the inflammatory response of macrophages to endotoxin.

Original languageEnglish
Article number35343
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Oct 17 2016
Externally publishedYes

Fingerprint

Toll-Like Receptor 4
Lipopolysaccharides
Clathrin
Macrophages
Endocytosis
Interferon Regulatory Factor-3
Porifera
Gene Expression Profiling
Cellular Structures
Gram-Negative Bacteria
Endotoxins
Cell Wall
Interferons
Small Interfering RNA
Cytokines
Genes
Proteins

ASJC Scopus subject areas

  • General

Cite this

Disabled-2 is a negative immune regulator of lipopolysaccharide-stimulated Toll-like receptor 4 internalization and signaling. / Hung, Wei Shan; Ling, Pin; Cheng, Ju Chien; Chang, Shy Shin; Tseng, Ching Ping.

In: Scientific Reports, Vol. 6, 35343, 17.10.2016.

Research output: Contribution to journalArticle

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