ORCID
- Luo, Shouqing: 0000-0002-7998-3059
Abstract
AbstractDegrading 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.
DOI
10.1038/s41422-021-00532-7
Publication Date
2021-07-08
Publication Title
Cell Research
Volume
31
Issue
9
ISSN
1001-0602
Embargo Period
2022-01-19
Organisational Unit
Peninsula Medical School
First Page
965
Last Page
979
Recommended Citation
Fu, Y., Chen, N., Wang, Z., Luo, S., Ding, Y., & Lu, B. (2021) 'Degradation of lipid droplets by chimeric autophagy-tethering compounds', Cell Research, 31(9), pp. 965-979. Available at: https://doi.org/10.1038/s41422-021-00532-7
