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dc.contributor.authorValionyte, E
dc.contributor.authorYang, Y
dc.contributor.authorGriffiths, SA
dc.contributor.authorBone, AT
dc.contributor.authorBarrow, ER
dc.contributor.authorSharma, Vikram
dc.contributor.authorLu, B
dc.contributor.authorLuo, Shouqing
dc.date.accessioned2022-03-07T11:23:12Z
dc.date.issued2021-12-03
dc.identifier.issn1350-9047
dc.identifier.issn1476-5403
dc.identifier.urihttp://hdl.handle.net/10026.1/18899
dc.description.abstract

<jats:title>Abstract</jats:title><jats:p>SQSTM1/p62, as a major autophagy receptor, forms droplets that are critical for cargo recognition, nucleation, and clearance. p62 droplets also function as liquid assembly platforms to allow the formation of autophagosomes at their surfaces. It is unknown how p62-droplet formation is regulated under physiological or pathological conditions. Here, we report that p62-droplet formation is selectively blocked by inflammatory toxicity, which induces cleavage of p62 by caspase-6 at a novel cleavage site D256, a conserved site across human, mouse, rat, and zebrafish. The N-terminal cleavage product is relatively stable, whereas the C-terminal product appears undetectable. Using a variety of cellular models, we show that the p62 N-terminal caspase-6 cleavage product (p62-N) plays a dominant-negative role to block p62-droplet formation. In vitro p62 phase separation assays confirm this observation. Dominant-negative regulation of p62-droplet formation by caspase-6 cleavage attenuates p62 droplets dependent autophagosome formation. Our study suggests a novel pathway to modulate autophagy through the caspase-6–p62 axis under certain stress stimuli.</jats:p>

dc.format.extent1211-1227
dc.format.mediumPrint-Electronic
dc.languageen
dc.language.isoen
dc.publisherSpringer Science and Business Media LLC
dc.subjectAnimals
dc.subjectAutophagosomes
dc.subjectAutophagy
dc.subjectCaspase 6
dc.subjectHumans
dc.subjectMice
dc.subjectRats
dc.subjectSequestosome-1 Protein
dc.subjectSignal Transduction
dc.subjectZebrafish
dc.titleThe caspase-6–p62 axis modulates p62 droplets based autophagy in a dominant-negative manner
dc.typejournal-article
dc.typeJournal Article
dc.typeResearch Support, Non-U.S. Gov't
plymouth.author-urlhttps://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000725940400002&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=11bb513d99f797142bcfeffcc58ea008
plymouth.issue6
plymouth.volume29
plymouth.publication-statusPublished
plymouth.journalCell Death & Differentiation
dc.identifier.doi10.1038/s41418-021-00912-x
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/Faculty of Health/School of Biomedical Sciences
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.dateAccepted2021-11-22
dc.rights.embargodate2022-3-8
dc.identifier.eissn1476-5403
dc.rights.embargoperiodNot known
rioxxterms.versionofrecord10.1038/s41418-021-00912-x
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2021-12-03
rioxxterms.typeJournal Article/Review
plymouth.funderTackling autophagy and apoptosis for the potential therapy of Huntington's Disease::MRC


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