Dataset Information

WW domain containing E3 ubiquitin protein ligase 1 (WWP1) negatively regulates TLR4-mediated TNF-? and IL-6 production by proteasomal degradation of TNF receptor associated factor 6 (TRAF6).

ABSTRACT:

Background

Toll-like receptors (TLRs) play a pivotal role in the defense against invading pathogens by detecting pathogen-associated molecular patterns (PAMPs). TLR4 recognizes lipopolysaccharides (LPS) in the cell walls of Gram-negative bacteria, resulting in the induction and secretion of proinflammatory cytokines such as TNF-? and IL-6. The WW domain containing E3 ubiquitin protein ligase 1 (WWP1) regulates a variety of cellular biological processes. Here, we investigated whether WWP1 acts as an E3 ubiquitin ligase in TLR-mediated inflammation.

Methodology/results

Knocking down WWP1 enhanced the TNF-? and IL-6 production induced by LPS, and over-expression of WWP1 inhibited the TNF-? and IL-6 production induced by LPS, but not by TNF-?. WWP1 also inhibited the I?B-?, NF-?B, and MAPK activation stimulated by LPS. Additionally, WWP1 could degrade TRAF6, but not IRAK1, in the proteasome pathway, and knocking down WWP1 reduced the LPS-induced K48-linked, but not K63-linked, polyubiquitination of endogenous TRAF6.

Conclusions/significance

We identified WWP1 as an important negative regulator of TLR4-mediated TNF-? and IL-6 production. We also showed that WWP1 functions as an E3 ligase when cells are stimulated with LPS by binding to TRAF6 and promoting K48-linked polyubiquitination. This results in the proteasomal degradation of TRAF6.

SUBMITTER: Lin XW

PROVIDER: S-EPMC3684580 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

WW domain containing E3 ubiquitin protein ligase 1 (WWP1) negatively regulates TLR4-mediated TNF-α and IL-6 production by proteasomal degradation of TNF receptor associated factor 6 (TRAF6).

Lin Xiao-Wen XW Xu Wei-Cheng WC Luo Jian-Gang JG Guo Xue-Jiao XJ Sun Tao T Zhao Xu-Li XL Fu Zhi-Jian ZJ

PloS one 20130617 6

<h4>Background</h4>Toll-like receptors (TLRs) play a pivotal role in the defense against invading pathogens by detecting pathogen-associated molecular patterns (PAMPs). TLR4 recognizes lipopolysaccharides (LPS) in the cell walls of Gram-negative bacteria, resulting in the induction and secretion of proinflammatory cytokines such as TNF-α and IL-6. The WW domain containing E3 ubiquitin protein ligase 1 (WWP1) regulates a variety of cellular biological processes. Here, we investigated whether WWP1 ...[more]

PMID: 23799152

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