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Toll-like Receptor 4 Ligands Down-regulate Fcγ Receptor IIb (FcγRIIb) via MARCH3 Protein-mediated Ubiquitination.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2016 Feb 19; Vol. 291 (8), pp. 3895-904. Date of Electronic Publication: 2015 Dec 22. - Publication Year :
- 2016
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Abstract
- Monocytes and macrophages are critical for the effectiveness of monoclonal antibody therapy. Responses to antibody-coated tumor cells are largely mediated by Fcγ receptors (FcγRs), which become activated upon binding to immune complexes. FcγRIIb is an inhibitory FcγR that negatively regulates these responses, and it is expressed on monocytes and macrophages. Therefore, deletion or down-regulation of this receptor may substantially enhance therapeutic outcomes. Here we screened a panel of Toll-like receptor (TLR) agonists and found that those selective for TLR4 and TLR8 could significantly down-regulate the expression of FcγRIIb. Upon further examination, we found that treatment of monocytes with TLR4 agonists could lead to the ubiquitination of FcγRIIb protein. A search of our earlier microarray database of monocytes activated with the TLR7/8 agonist R-848 (in which FcγRIIb was down-regulated) revealed an up-regulation of membrane-associated ring finger (C3HC4) 3 (MARCH3), an E3 ubiquitin ligase. Therefore, we tested whether LPS treatment could up-regulate MARCH3 in monocytes and whether this E3 ligase was involved with LPS-mediated FcγRIIb down-regulation. The results showed that LPS activation of TLR4 significantly increased MARCH3 expression and that siRNA against MARCH3 prevented the decrease in FcγRIIb following LPS treatment. These data suggest that activation of TLR4 on monocytes can induce a rapid down-regulation of FcγRIIb protein and that this involves ubiquitination.<br /> (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- Down-Regulation physiology
Gene Expression Regulation, Enzymologic drug effects
Humans
Toll-Like Receptor 4 metabolism
Toll-Like Receptor 7 metabolism
Toll-Like Receptor 8 metabolism
Ubiquitin-Protein Ligases
Ubiquitination physiology
Carrier Proteins metabolism
Down-Regulation drug effects
Lipopolysaccharides pharmacology
Membrane Proteins metabolism
Monocytes metabolism
Receptors, IgG biosynthesis
Toll-Like Receptor 4 agonists
Ubiquitination drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 291
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 26694610
- Full Text :
- https://doi.org/10.1074/jbc.M115.701151