{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T01:34:04Z","timestamp":1793324044056,"version":"4.5.0"},"reference-count":66,"publisher":"National Academy of Sciences","issue":"50","license":[{"start":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T00:00:00Z","timestamp":1765238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["2640\/23"],"award-info":[{"award-number":["2640\/23"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019180","name":"EC | ERC | HORIZON EUROPE European Research Council","doi-asserted-by":"publisher","award":["UbWan 101142726"],"award-info":[{"award-number":["UbWan 101142726"]}],"id":[{"id":"10.13039\/100019180","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,12,16]]},"abstract":"<jats:p>\n                    UBB\n                    <jats:sup>+1<\/jats:sup>\n                    , a ubiquitin variant protein resulting from a frameshift in the ubiquitin-B gene, is a pathological hallmark of Alzheimer disease (AD). At the cellular level, UBB\n                    <jats:sup>+1<\/jats:sup>\n                    disrupts the ubiquitin\u2013proteasome system while inducing autophagy. Notably, UBB\n                    <jats:sup>+1<\/jats:sup>\n                    itself is secreted via autophagosome-like vesicles. Here, we demonstrate that UBB\n                    <jats:sup>+1<\/jats:sup>\n                    can be removed from the cell by degradative and secretory autophagy. Sequestosome 1 (SQSTM1)\/p62 functions as a pivotal ubiquitin receptor for UBB\n                    <jats:sup>+1<\/jats:sup>\n                    , recognizing its ubiquitin domain and facilitating loading into autophagosomes. Oligomerization of SQSTM1\/p62 was critical to isolate UBB\n                    <jats:sup>+1<\/jats:sup>\n                    in bodies preventing its aggregation. Intriguingly, both gain- and loss-of-function SQSTM1\/p62 suppressed UBB\n                    <jats:sup>+1<\/jats:sup>\n                    secretion, causing intracellular retention: SQSTM1\/p62 knockout led to UBB\n                    <jats:sup>+1<\/jats:sup>\n                    accumulation in insoluble aggregates, while its overexpression promoted the formation of p62-UBB\n                    <jats:sup>+1<\/jats:sup>\n                    bodies. We further identified distinct roles for SNARE-mediated membrane fusion in secretory autophagy of UBB\n                    <jats:sup>+1<\/jats:sup>\n                    . Specifically, the R-SNARE SEC22B and the Q-SNAREs Syntaxin-4 and SNAP23 participated in UBB\n                    <jats:sup>+1<\/jats:sup>\n                    exocytosis. Disruption of SEC22B impaired the fusion of UBB\n                    <jats:sup>+1<\/jats:sup>\n                    -containing autophagosomes with the plasma membrane, reducing UBB\n                    <jats:sup>+1<\/jats:sup>\n                    secretion without affecting its intracellular turnover. Inhibition of lysosomes partially stabilized UBB\n                    <jats:sup>+1<\/jats:sup>\n                    indicating that degradation and secretion are complementary processes that determine the fate of UBB\n                    <jats:sup>+1<\/jats:sup>\n                    . This study elucidates the dual roles of autophagy in managing neurotoxic proteins, highlighting SQSTM1\/p62 as a key mediator of UBB\n                    <jats:sup>+1<\/jats:sup>\n                    trafficking and secretion. Although ubiquitin typically acts as a degradation signal, our findings reveal a rare instance of a ubiquitin-related protein driving secretory autophagy. These findings advance our understanding of cellular mechanisms underlying the clearance of misfolded proteins in neurodegenerative diseases.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2504528122","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T18:55:06Z","timestamp":1765306506000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":8,"title":["Molecular mechanisms underlying p62-dependent secretion of the Alzheimer-associated ubiquitin variant UBB\n                    <sup>+1<\/sup>"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6196-7651","authenticated-orcid":false,"given":"Ajay R.","family":"Wagh","sequence":"first","affiliation":[{"name":"The Faculty of Biology, Technion \u2013 Israel Institute of Technology","place":["Haifa, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1222-8104","authenticated-orcid":false,"given":"Michael H.","family":"Glickman","sequence":"additional","affiliation":[{"name":"The Faculty of Biology, Technion \u2013 Israel Institute of Technology","place":["Haifa, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,12,9]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm4024"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2017.11.018"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.11205"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aal4677"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2015.04.016"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1159\/000346707"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1007-1102"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.04.026"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.4161\/cc.8.13.8892"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M702824200"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.10.035"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(96)30015-7"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.11.5857"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.18.8055-8068.2004"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M704973200"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C109.073627"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.3858\/emm.2012.44.2.031"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1001-939"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cellbio-100818-125242"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2018.02.008"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2017.12.006"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2017.12.018"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.17.7552"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-014-0313-y"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-41545-7"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.279.5348.242"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.650730"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2008.00276.x"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2015.00026"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-012-1003-7"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2023.194936"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2010.06.004"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2617"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2005.03.014"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201695081"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.076489"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3048"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.11.021"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2010.01050.x"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.11.001"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201211160"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2022.2079337"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202301936"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201798308"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.08941"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15672"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.6b04194"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2018.06.153"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.7.3.14487"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.34.20235"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2012.09.012"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells8010040"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M802182200"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST0320728"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1359\/JBMR.041205"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.113935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R. Wagh M. H. Glickman Underlying data for \u201cMolecular mechanisms underlying p62-dependent secretion of the Alzheimer-associated ubiquitin variant UBB+1\u201d. Figshare. https:\/\/doi.org\/10.6084\/m9.figshare.30704243. 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