Toll-like Receptor 4 Ligands Down-regulate Fcγ Receptor IIb (FcγRIIb) via MARCH3 Protein-mediated Ubiquitination
Autor: | Kavin Fatehchand, Gregory N. Dietsch, Saranya Elavazhagan, Jonathan P. Butchar, Huiqing Fang, Robert M. Hershberg, Susheela Tridandapani, Xiaokui Mo, Li Ren, John P. Vasilakos |
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Rok vydání: | 2016 |
Předmět: |
Lipopolysaccharides
0301 basic medicine Ubiquitin-Protein Ligases Immunology Fc receptor Down-Regulation Biochemistry Gene Expression Regulation Enzymologic Monocytes 03 medical and health sciences medicine Humans Receptor Molecular Biology Toll-like receptor biology Monocyte Receptors IgG Ubiquitination Membrane Proteins Cell Biology TLR7 TLR8 Ubiquitin ligase Cell biology Toll-Like Receptor 4 030104 developmental biology medicine.anatomical_structure Toll-Like Receptor 7 Toll-Like Receptor 8 biology.protein TLR4 Carrier Proteins |
Zdroj: | Journal of Biological Chemistry. 291:3895-3904 |
ISSN: | 0021-9258 |
DOI: | 10.1074/jbc.m115.701151 |
Popis: | 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. |
Databáze: | OpenAIRE |
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