{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:06:07Z","timestamp":1790813167640,"version":"4.1.0"},"reference-count":39,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2014,7,28]],"date-time":"2014-07-28T00:00:00Z","timestamp":1406505600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30AG024824, P30AG013283, P30DK034933, P30DK089503, P30CA046592 and R21AG045432"],"award-info":[{"award-number":["P30AG024824, P30AG013283, P30DK034933, P30DK089503, P30CA046592 and R21AG045432"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000863","name":"Ellison Medical Foundation","doi-asserted-by":"publisher","award":["AG-NS-0932-12"],"award-info":[{"award-number":["AG-NS-0932-12"]}],"id":[{"id":"10.13039\/100000863","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001424","name":"American Liver Foundation","doi-asserted-by":"publisher","award":["Liver Scholar"],"award-info":[{"award-number":["Liver Scholar"]}],"id":[{"id":"10.13039\/100001424","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2014,9]]},"abstract":"\n \n \n Autophagy is a homeostatic process that is important for degrading protein aggregates, nutrient deposits, dysfunctional organelles and several signaling molecules. p62\/sequestosome\u20101 is a protein that binds to several autophagy substrates, such as ubiquitinated proteins, damaged mitochondria and signaling molecules such as an Nrf2 inhibitor Keap1, promoting their autophagic degradation. Sestrin2, a stress\u2010inducible protein, has recently been shown to bind to p62 and promote autophagic degradation of such p62 targets. Because Sestrin2 is a metabolic regulator that suppresses diverse age\u2010 and obesity\u2010associated pathologies, the autophagy\u2010controlling function of Sestrin2 may be important for its other physiological functions. However, the molecular mechanism of how Sestrin2 can promote clearance of p62\u2010associated proteins has been unclear. Here we show that Sestrin2 physically associates with Unc\u201051\u2010like protein kinase 1 (\n ULK<\/jats:styled-content>\n 1) and p62 to form a complex in which both Sestrin2 and p62 become phosphorylated by\n ULK<\/jats:styled-content>\n 1 at multiple sites. Ser403 of p62, whose phosphorylation is known to promote autophagic degradation of p62 and its targets, is among the sites phosphorylated by\n ULK<\/jats:styled-content>\n 1.\n ULK<\/jats:styled-content>\n 1\u2010mediated p62 phosphorylation was facilitated by Sestrin2 in cells as well as in\n in\u00a0vitro<\/jats:italic>\n kinase assays. Consistent with this finding, oligomycin\u2010induced energy deprivation, which strongly activates\n ULK<\/jats:styled-content>\n 1, provoked a robust Ser403 phosphorylation of p62 in wild\u2010type mouse embryonic fibroblasts. However, in\n ULK<\/jats:styled-content>\n 1\/2\u2010 and Sestrin2\u2010deficient mouse embryonic fibroblasts, oligomycin\u2010induced p62 phosphorylation was dramatically attenuated, suggesting that endogenous Sestrin2\u2010\n ULK<\/jats:styled-content>\n 1\/2 mainly mediates p62 phosphorylation in response to energetic stress. Taken together, this study identifies\n ULK<\/jats:styled-content>\n 1 as a new p62 Ser403 kinase and establishes Sestrin2 as a promoter of\n ULK<\/jats:styled-content>\n 1\u2010mediated p62 phosphorylation.\n <\/jats:p>\n <\/jats:sec>\n \n Structured digital abstract<\/jats:title>\n \n \n \n \n ULK1<\/jats:ext-link>\n \u00a0\n physically interacts<\/jats:ext-link>\n \u00a0with\u00a0\n Sestrin2<\/jats:ext-link>\n \u00a0by\u00a0\n pull down<\/jats:ext-link>\n \u00a0(\n View interaction<\/jats:ext-link>\n )\n <\/jats:p>\n <\/jats:list-item>\n \n \n p62<\/jats:ext-link>\n \u00a0\n physically interacts<\/jats:ext-link>\n \u00a0with\u00a0\n Sestrin2<\/jats:ext-link>\n \u00a0by\u00a0\n anti tag coimmunoprecipitation<\/jats:ext-link>\n \u00a0(\n 1<\/jats:ext-link>\n ,\u00a0\n 2<\/jats:ext-link>\n )\n <\/jats:p>\n <\/jats:list-item>\n \n \n p62<\/jats:ext-link>\n \u00a0\n physically interacts<\/jats:ext-link>\n \u00a0with\u00a0\n ULK1<\/jats:ext-link>\n \u00a0by\u00a0\n anti tag coimmunoprecipitation<\/jats:ext-link>\n \u00a0(\n View interaction<\/jats:ext-link>\n )\n <\/jats:p>\n <\/jats:list-item>\n \n \n Sestrin2<\/jats:ext-link>\n \u00a0\n physically interacts<\/jats:ext-link>\n \u00a0with\u00a0\n p62<\/jats:ext-link>\n \u00a0and\u00a0\n ULK1<\/jats:ext-link>\n \u00a0by\u00a0\n anti bait coip<\/jats:ext-link>\n \u00a0(\n View interaction<\/jats:ext-link>\n )\n <\/jats:p>\n <\/jats:list-item>\n \n \n Sestrin2<\/jats:ext-link>\n \u00a0\n physically interacts<\/jats:ext-link>\n \u00a0with\u00a0\n ULK1<\/jats:ext-link>\n ,\u00a0\n FIP200<\/jats:ext-link>\n \u00a0and\u00a0\n Atg13<\/jats:ext-link>\n \u00a0by\u00a0\n anti tag coimmunoprecipitation<\/jats:ext-link>\n \u00a0(\n View interaction<\/jats:ext-link>\n )\n <\/jats:p>\n <\/jats:list-item>\n \n \n p62<\/jats:ext-link>\n \u00a0\n physically interacts<\/jats:ext-link>\n \u00a0with\u00a0\n ULK1<\/jats:ext-link>\n \u00a0and\u00a0\n Sestrin2<\/jats:ext-link>\n \u00a0by\u00a0\n anti tag coimmunoprecipitation<\/jats:ext-link>\n \u00a0(\n View interaction<\/jats:ext-link>\n )\n <\/jats:p>\n <\/jats:list-item>\n \n \n ULK1<\/jats:ext-link>\n \u00a0\n physically interacts<\/jats:ext-link>\n \u00a0with\u00a0\n Sestrin2<\/jats:ext-link>\n \u00a0by\u00a0\n anti tag coimmunoprecipitation<\/jats:ext-link>\n \u00a0(\n 1<\/jats:ext-link>\n ,\u00a0\n 2<\/jats:ext-link>\n ,\u00a0\n 3<\/jats:ext-link>\n )\n <\/jats:p>\n <\/jats:list-item>\n \n \n p62<\/jats:ext-link>\n \u00a0\n physically interacts<\/jats:ext-link>\n \u00a0with\u00a0\n Sestrin2<\/jats:ext-link>\n \u00a0by\u00a0\n pull down<\/jats:ext-link>\n \u00a0(\n View interaction<\/jats:ext-link>\n )\n <\/jats:p>\n <\/jats:list-item>\n \n \n p62<\/jats:ext-link>\n \u00a0\n physically interacts<\/jats:ext-link>\n \u00a0with\u00a0\n Sestrin2<\/jats:ext-link>\n \u00a0by\u00a0\n anti tag coimmunoprecipitation<\/jats:ext-link>\n \u00a0(\n View interaction<\/jats:ext-link>\n )\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/febs.12905","type":"journal-article","created":{"date-parts":[[2014,7,4]],"date-time":"2014-07-04T12:03:11Z","timestamp":1404475391000},"page":"3816-3827","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":119,"title":["Sestrin2 promotes Unc\u201051\u2010like kinase 1 mediated phosphorylation of p62\/sequestosome\u20101"],"prefix":"10.1111","volume":"281","author":[{"given":"Seung\u2010Hyun","family":"Ro","sequence":"first","affiliation":[{"name":"Department of Molecular and Integrative Physiology University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian A.","family":"Semple","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haewon","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haeli","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwan\u2010Woo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myungjin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong Sig","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology University of Michigan Ann Arbor MI USA"},{"name":"Department of Obstetrics and Gynecology Soonchunhyang University Seoul Hospital Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Hee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,7,28]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature06639"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2013.168"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.05.023"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.7.3.14487"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2021"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00248-10"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.08.018"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1182228"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.08.004"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.06.028"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0032035"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.8.10.8498"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.12.002"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2011.07.039"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.04.015"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2013.08.003"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201000097"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2152"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01082-08"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M900573200"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e08-12-1248"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e08-12-1249"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00620-10"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200712064"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.09.049"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1196371"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/1478-811X-10-7"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(93)80398-E"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.4771"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201002100"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2757"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2010.338"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2013.12.011"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201009067"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E02-05-0295"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.149.2.423"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.23066"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.26563"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.24811"}],"container-title":["The 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