Volume 31, No 9, Sep 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 9, September 2021: 965-979   |  Open Access

ORIGINAL ARTICLES

Degradation of lipid droplets by chimeric autophagy-tethering compounds

Yuhua Fu¹ , Ningxie Chen¹ , Ziying Wang¹ , Shouqing Luo² , Yu Ding^1,* , Boxun Lu^1,*

¹State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Huashan Hospital, School of Life Sciences, Fudan University, Shanghai, China
²Peninsula Schools of Medicine and Dentistry, Institute of Translational and Stratified Medicine, University of Plymouth, Plymouth, UK
Correspondence: Yu Ding(yuding@fudan.edu.cn)Boxun Lu(luboxun@fudan.edu.cn)

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.

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

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