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dc.contributor.authorFu, Y
dc.contributor.authorChen, N
dc.contributor.authorWang, Z
dc.contributor.authorLuo, Shouqing
dc.contributor.authorDing, Y
dc.contributor.authorLu, B
dc.date.accessioned2022-01-18T12:23:11Z
dc.date.issued2021-07-08
dc.identifier.issn1001-0602
dc.identifier.issn1748-7838
dc.identifier.urihttp://hdl.handle.net/10026.1/18574
dc.description.abstract

<jats:title>Abstract</jats:title><jats:p>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.</jats:p>

dc.format.extent965-979
dc.format.mediumPrint-Electronic
dc.languageen
dc.language.isoen
dc.publisherShanghai Institutes for Biological Sciences
dc.subjectAnimals
dc.subjectAutophagosomes
dc.subjectAutophagy
dc.subjectChimera
dc.subjectLipid Droplets
dc.subjectLipid Metabolism
dc.subjectMice
dc.subjectProteins
dc.titleDegradation of lipid droplets by chimeric autophagy-tethering compounds
dc.typejournal-article
dc.typeJournal Article
dc.typeResearch Support, Non-U.S. Gov't
plymouth.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/34239073
plymouth.issue9
plymouth.volume31
plymouth.publication-statusPublished
plymouth.journalCell Research
dc.identifier.doi10.1038/s41422-021-00532-7
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/Faculty of Health
plymouth.organisational-group/Plymouth/Faculty of Health/Peninsula Medical School
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
plymouth.organisational-group/Plymouth/Research Groups
plymouth.organisational-group/Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)
plymouth.organisational-group/Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)/CBR
plymouth.organisational-group/Plymouth/Users by role
plymouth.organisational-group/Plymouth/Users by role/Academics
plymouth.organisational-group/Plymouth/Users by role/Researchers in ResearchFish submission
dc.publisher.placeEngland
dcterms.dateAccepted2021-06-18
dc.rights.embargodate2022-1-19
dc.identifier.eissn1748-7838
dc.rights.embargoperiodNot known
rioxxterms.versionofrecord10.1038/s41422-021-00532-7
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2021-07-08
rioxxterms.typeJournal Article/Review


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