Toll-like Receptor 8 Stability Is Regulated by Ring Finger 216 in Response to Circulating MicroRNAs.

American Journal of Respiratory Cell and Molecular Biology
John EvankovichBill B Chen

Abstract

TLR8 (Toll-like receptor 8) is an intracellular pattern recognition receptor that senses RNA in endosomes to initiate innate immune signaling through NF-κB, and mechanisms regulating TLR8 protein abundance are not completely understood. Protein degradation is a cellular process controlling protein concentrations, accomplished largely through ubiquitin transfer directed by E3 ligase proteins to substrates. In the present study, we show that TLR8 has a short half-life in THP-1 monocytes (∼1 h) and that TLR8 is ubiquitinated and degraded in the proteasome. Treatment with the TLR8 agonist R848 causes rapid depletion of TLR8 concentrations at early time points, an effect blocked by proteasomal inhibition. We show a novel role for RNF216 (ring finger protein 216), an E3 ligase that targets TLR8 for ubiquitination and degradation. RNF216 overexpression reduces TLR8 concentrations, whereas RNF216 knockdown stabilizes TLR8. We describe a potential role for TLR8 activation by circulating RNA ligands in humans with acute respiratory distress syndrome (ARDS): Plasma and extracted RNA fractions from subjects with ARDS activated TLR8 in vitro. MicroRNA (miRNA) expression profiling revealed several circulating miRNAs from subjects with ARDS. ...Continue Reading

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Citations

Nov 18, 2020·American Journal of Respiratory Cell and Molecular Biology·Binchan HeXin Su
Mar 17, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Dengfeng LiJia-Da Li
Mar 19, 2021·American Journal of Respiratory and Critical Care Medicine·Robinder G KhemaniRémi Coudroy
Oct 7, 2021·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Maria L DiasFiona B McDonald

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Datasets Mentioned

BETA
PRO10110387
GSE47625
and

Methods Mentioned

BETA
ubiquitination
pulldown
pulldowns
transfection

Software Mentioned

GraphPad
Prism
nSolver
TargetScan

Related Concepts

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