Degradation of lipid droplets by chimeric autophagy-tethering compounds

Yuhua Fu,Boxun Lu,Ningxie Chen,Ziying Wang,Shouqing Luo,Yu Ding

doi:10.1038/s41422-021-00532-7

Yuhua Fu, Boxun Lu + Show 4 more

Open Access

https://doi.org/10.1038/s41422-021-00532-7

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Abstract

Degrading pathogenic proteins by degrader technologies such as PROTACs (proteolysis-targeting chimeras) provides promising therapeutic strategies, but selective degradation of non-protein pathogenic biomolecules has been challenging. Here, we demonstrate a novel strategy to degrade non-protein biomolecules by autophagy-tethering compounds (ATTECs), using lipid droplets (LDs) as an exemplar target. LDs are ubiquitous cellular structures storing lipids and could be degraded by autophagy. We hypothesized that compounds interacting with both the LDs and the key autophagosome protein LC3 may enhance autophagic degradation of LDs. We designed and synthesized such compounds by connecting LC3-binding molecules to LD-binding probes via a linker. These compounds were capable of clearing LDs almost completely and rescued LD-related phenotypes in cells and in two independent mouse models with hepatic lipidosis. We further confirmed that the mechanism of action of these compounds was mediated through LC3 and autophagic degradation. Our proof-of-concept study demonstrates the capability of degrading LDs by ATTECs. Conceptually, this strategy could be applied to other protein and non-protein targets.

Highlights

Selective degradation of pathogenic proteins by small-molecule compounds such as PROTACs provides unprecedented opportunities in drug discovery.1 there has been a lack of degrader technologies to target non-protein biomolecules, which may have important pathological functions
We have recently demonstrated the concept of autophagytethering compounds (ATTECs) as a potential strategy to harness autophagy to degrade specific disease proteins of interest (POI)
We investigated whether lipid droplets (LDs)·autophagy-tethering compounds (ATTECs) enhance the interaction between LC3 and TAG, a core lipid component of LDs that may recruit SIII and SIV for LD staining

Summary

INTRODUCTION

Selective degradation of pathogenic proteins by small-molecule compounds such as PROTACs (proteolysis-targeting chimeras) provides unprecedented opportunities in drug discovery. there has been a lack of degrader technologies to target non-protein biomolecules, which may have important pathological functions. Selective degradation of pathogenic proteins by small-molecule compounds such as PROTACs (proteolysis-targeting chimeras) provides unprecedented opportunities in drug discovery.. We have recently demonstrated the concept of autophagytethering compounds (ATTECs) as a potential strategy to harness autophagy to degrade specific disease proteins of interest (POI).. ATTECs tether the POI with autophagosomes through their direct binding to the POI and the key autophagosome-associated protein LC3. This proof-of-concept study established a high-throughput screening strategy to identify ATTECs targeting the mutant HTT protein (mHTT), which is the Huntington’s disease (HD)-causing protein.. The LD degradation achieved by LD·ATTECs may demonstrate the concept of using ATTECs for selective degradation of non-protein biomolecules, opening new avenues for drug discovery

RESULTS

DISCUSSION

DMSO C4 SIII

MATERIAL AND METHODS