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dc.contributor.authorJain, Ashish
dc.contributor.authorRusten, Tor Erik
dc.contributor.authorKatheder, Nadja Sandra
dc.contributor.authorElvenes, Julianne
dc.contributor.authorBruun, Jack-Ansgar
dc.contributor.authorSjøttem, Eva
dc.contributor.authorLamark, Trond
dc.contributor.authorJohansen, Terje
dc.date.accessioned2022-04-11T13:41:37Z
dc.date.available2022-04-11T13:41:37Z
dc.date.issued2015-04-30
dc.description.abstractThe selective autophagy receptor p62/sequestosome 1 (SQSTM1) interacts directly with LC3 and is involved in oxidative stress signaling in two ways in mammals. First, p62 is transcriptionally induced upon oxidative stress by the NF-E2-related factor 2 (NRF2) by direct binding to an antioxidant response element in the p62 promoter. Second, p62 accumulation, occurring when autophagy is impaired, leads to increased p62 binding to the NRF2 inhibitor KEAP1, resulting in reduced proteasomal turnover of NRF2. This gives chronic oxidative stress signaling through a feed forward loop. Here, we show that the Drosophila p62/SQSTM1 orthologue, Ref(2)P, interacts directly with DmAtg8a via an LC3-interacting region motif, supporting a role for Ref(2)P in selective autophagy. The ref(2)P promoter also contains a functional antioxidant response element that is directly bound by the NRF2 orthologue, CncC, which can induce ref(2)P expression along with the oxidative stress-associated gene gstD1. However, distinct from the situation in mammals, Ref(2)P does not interact directly with DmKeap1 via a KEAP1-interacting region motif; nor does ectopically expressed Ref(2)P or autophagy deficiency activate the oxidative stress response. Instead, DmAtg8a interacts directly with DmKeap1, and DmKeap1 is removed upon programmed autophagy in Drosophila gut cells. Strikingly, CncC induced increased Atg8a levels and autophagy independent of TFEB/MitF in fat body and larval gut tissues. Thus, these results extend the intimate relationship between oxidative stress-sensing NRF2/CncC transcription factors and autophagy and suggest that NRF2/CncC may regulate autophagic activity in other organisms too.en_US
dc.identifier.citationJain A, Rusten TE, Katheder NS, Elvenes J, Bruun JA, Sjøttem E, Lamark T, Johansen T. P62/sequestosome-1, autophagy-related gene 8, and autophagy in Drosophila are regulated by nuclear factor erythroid 2-related factor 2(NRF2), independent of transcription factor TFEB. Journal of Biological Chemistry. 2015;290(24):14945-14962en_US
dc.identifier.cristinIDFRIDAID 1259554
dc.identifier.doi10.1074/jbc.M115.656116
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.urihttps://hdl.handle.net/10037/24754
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.relation.journalJournal of Biological Chemistry
dc.relation.projectIDNorges forskningsråd: 179571en_US
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2015 The Author(s)en_US
dc.titleP62/sequestosome-1, autophagy-related gene 8, and autophagy in Drosophila are regulated by nuclear factor erythroid 2-related factor 2(NRF2), independent of transcription factor TFEBen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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