Cell Chemical Biology
Volume 28, Issue 2, 18 February 2021, Pages 202-212.e6
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Article
Profiling of MicroRNA Targets Using Activity-Based Protein Profiling: Linking Enzyme Activity to MicroRNA-185 Function

https://doi.org/10.1016/j.chembiol.2020.12.009Get rights and content
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Highlights

  • Identified serine hydrolases that are regulated by the immunometabolic microRNA-185

  • microRNA-regulated enzymes are involved in lipid and endocannabinoid metabolism

  • Showed that inhibition of microRNA-targeted enzymes is antiviral

  • Activity-based protein profiling identifies pharmacological targets of a microRNA

Summary

MicroRNAs (miRNAs) act as cellular signal transducers through repression of protein translation. Elucidating targets using bioinformatics and traditional quantitation methods is often insufficient to uncover global miRNA function. Herein, alteration of protein function caused by miRNA-185 (miR-185), an immunometabolic miRNA, was determined using activity-based protein profiling, transcriptomics, and lipidomics. Fluorophosphonate-based activity-based protein profiling of miR-185-induced changes to human liver cells revealed that exclusively metabolic serine hydrolase enzymes were regulated in activity, some with roles in lipid and endocannabinoid metabolism. Lipidomic analysis linked enzymatic changes to levels of cellular lipid species, such as components of very-low-density lipoprotein particles. Additionally, inhibition of one miR-185 target, monoglyceride lipase, led to decreased hepatitis C virus levels in an infectious model. Overall, the approaches used here were able to identify key functional changes in serine hydrolases caused by miR-185 that are targetable pharmacologically, such that a small molecule inhibitor can recapitulate the miRNA phenotype.

Keywords

microRNAs
microRNA signaling
miR-185
inhibitor
activity-based protein profiling
lipids
metabolism
antiviral
monoglyceride lipase

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