{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T14:54:37Z","timestamp":1793717677629,"version":"4.6.1"},"reference-count":62,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T00:00:00Z","timestamp":1681689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82192861"],"award-info":[{"award-number":["82192861"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82071051"],"award-info":[{"award-number":["82071051"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81773704"],"award-info":[{"award-number":["81773704"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32071220"],"award-info":[{"award-number":["32071220"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31701230"],"award-info":[{"award-number":["31701230"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31900936"],"award-info":[{"award-number":["31900936"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["Z200019"],"award-info":[{"award-number":["Z200019"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The ankle\u2010link complex (ALC) consists of USH2A, WHRN, PDZD7, and ADGRV1 and plays an important role in hair cell development. At present, its architectural organization and signaling role remain unclear. By establishing <jats:italic>Adgrv1<\/jats:italic> Y6236fsX1 mutant mice as a model of the deafness\u2010associated human Y6244fsX1 mutation, the authors show here\u00a0that the Y6236fsX1 mutation disrupts the interaction between adhesion G protein\u2010coupled receptor V subfamily member 1 (ADGRV1) and other ALC components, resulting in stereocilia disorganization and mechanoelectrical transduction (MET) deficits. Importantly, ADGRV1 inhibits WHRN phosphorylation through regional cAMP\u2010PKA signaling, which in turn regulates the ubiquitination and stability of USH2A via local signaling compartmentalization, whereas ADGRV1 Y6236fsX1 does not. Yeast two\u2010hybrid screening identified the E3 ligase WDSUB1 that binds to WHRN and regulates the ubiquitination of USH2A in a WHRN phosphorylation\u2010dependent manner. Further FlAsH\u2010BRET assay, NMR spectrometry, and mutagenesis analysis provided insights into the architectural organization of ALC and interaction motifs at single\u2010residue resolution. In conclusion, the present data suggest that ALC organization\u00a0and accompanying local signal transduction play important roles in regulating the stability of the ALC.<\/jats:p>","DOI":"10.1002\/advs.202205993","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T04:55:20Z","timestamp":1681707320000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Deafness\u2010Associated ADGRV1 Mutation Impairs USH2A Stability through Improper Phosphorylation of WHRN and WDSUB1 Recruitment"],"prefix":"10.1002","volume":"10","author":[{"given":"Ying","family":"Guan","sequence":"first","affiliation":[{"name":"Key Laboratory Experimental Teratology of the Ministry of Education Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University   Jinan 250012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai\u2010Bo","family":"Du","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology Shandong University School of Life Sciences  Qingdao 266237 China"},{"name":"Air Force Medical Center  PLA Beijing 100142 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory Experimental Teratology of the Ministry of Education Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University   Jinan 250012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Zhu","family":"Wang","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics Hefei National Research Center for Interdisciplinary Sciences at the Microscale School of Life Sciences University of Science and Technology of China  Hefei 230022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Ren","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology Shandong University School of Life Sciences  Qingdao 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen\u2010Wen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery Shandong Provincial ENT Hospital Cheeloo College of Medicine Shandong University  Jinan 250014 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory Experimental Teratology of the Ministry of Education Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University   Jinan 250012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia\u2010Hai","family":"Zhang","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics Hefei National Research Center for Interdisciplinary Sciences at the Microscale School of Life Sciences University of Science and Technology of China  Hefei 230022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen\u2010Tao","family":"An","sequence":"additional","affiliation":[{"name":"Advanced Medical Research Institute Cheeloo College of Medicine Shandong University  Jinan 250012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na\u2010Na","family":"Li","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology Shandong University School of Life Sciences  Qingdao 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010Xue","family":"Zeng","sequence":"additional","affiliation":[{"name":"Key Laboratory Experimental Teratology of the Ministry of Education Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University   Jinan 250012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[{"name":"School of Life Sciences IDG\/McGovern Institute for Brain Research at Tsinghua Tsinghua University  Beijing 100084 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Xiao","family":"Sun","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology Shandong University School of Life Sciences  Qingdao 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan\u2010Fei","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology Shandong University School of Life Sciences  Qingdao 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory Experimental Teratology of the Ministry of Education Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University   Jinan 250012 China"},{"name":"Key Laboratory Experimental Teratology of the Ministry of Education Department of Physiology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University  Jinan 250012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences Moran Eye Center University of Utah  Salt Lake City UT 84132 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Xiong","sequence":"additional","affiliation":[{"name":"School of Life Sciences IDG\/McGovern Institute for Brain Research at Tsinghua Tsinghua University  Beijing 100084 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Yu","sequence":"additional","affiliation":[{"name":"Key Laboratory Experimental Teratology of the Ministry of Education Department of Physiology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University  Jinan 250012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u2010Jie","family":"Chai","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory for Developmental Genes and Human Disease Institute of Life Sciences Jiangsu Province High\u2010Tech Key Laboratory for Bio\u2010Medical Research Southeast University  Nanjing 210096 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010Ming","family":"Tu","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics Hefei National Research Center for Interdisciplinary Sciences at the Microscale School of Life Sciences University of Science and Technology of China  Hefei 230022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3572-1580","authenticated-orcid":false,"given":"Jin\u2010Peng","family":"Sun","sequence":"additional","affiliation":[{"name":"Key Laboratory Experimental Teratology of the Ministry of Education Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University   Jinan 250012 China"},{"name":"Advanced Medical Research Institute Cheeloo College of Medicine Shandong University  Jinan 250012 China"},{"name":"Department of Physiology and Pathophysiology School of Basic Medical Sciences Peking University Key Laboratory of Molecular Cardiovascular Science Ministry of Education  Beijing 100191 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi\u2010Gang","family":"Xu","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology Shandong University School of Life Sciences  Qingdao 266237 China"},{"name":"Shandong Provincial Collaborative Innovation Center of Cell Biology Shandong Normal University  Jinan 250014 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,4,17]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4419-7913-1_6"},{"key":"e_1_2_10_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-012-9911-5"},{"key":"e_1_2_10_1_3","doi-asserted-by":"publisher","DOI":"10.1124\/pr.114.009647"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1086\/381685"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10347"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(01)00397-X"},{"key":"e_1_2_10_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2004.02.005"},{"key":"e_1_2_10_4_3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2005.02.006"},{"key":"e_1_2_10_4_4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2004.02875.x"},{"key":"e_1_2_10_4_5","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0693-06.2006"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1210\/mend.14.9.0511"},{"key":"e_1_2_10_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M108929200"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0342-07.2007"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.76.3.1506"},{"key":"e_1_2_10_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2295"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.20513"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2443.2007.01046.x"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3071-12.2012"},{"key":"e_1_2_10_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt629"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.549816"},{"key":"e_1_2_10_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1318501110"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-18-07013.2001"},{"key":"e_1_2_10_12_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-10-04054.2003"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000955"},{"key":"e_1_2_10_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.610535"},{"key":"e_1_2_10_13_3","first-page":"6944","volume":"24","author":"Zou J. H.","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"e_1_2_10_13_4","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx110"},{"key":"e_1_2_10_13_5","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2019.02.007"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.247973"},{"key":"e_1_2_10_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.11.036"},{"key":"e_1_2_10_14_3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1421785112"},{"key":"e_1_2_10_14_4","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.14227"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1665"},{"key":"e_1_2_10_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.07.035"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abe4091"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2569-1"},{"key":"e_1_2_10_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-00464-8"},{"key":"e_1_2_10_17_3","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02401-7"},{"key":"e_1_2_10_17_4","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-03083-w"},{"key":"e_1_2_10_17_5","doi-asserted-by":"publisher","DOI":"10.1038\/nature17198"},{"key":"e_1_2_10_17_6","doi-asserted-by":"publisher","DOI":"10.1038\/nature17154"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12104-016-9701-z"},{"key":"e_1_2_10_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2017.08.013"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a033142"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.280.5370.1753"},{"key":"e_1_2_10_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi416"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(00)00398-5"},{"key":"e_1_2_10_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsb906"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2148-10-331"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.02.011"},{"key":"e_1_2_10_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.07.035"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1185988"},{"key":"e_1_2_10_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2017.12.004"},{"key":"e_1_2_10_24_3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.07.043"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1124\/pharmrev.120.000086"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.09.037"},{"key":"e_1_2_10_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2298"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201901657RR"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.10.041"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3833-08.2008"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.19.11400"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.33432"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202205993","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T13:46:02Z","timestamp":1759758362000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202205993"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,17]]},"references-count":62,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2023,6]]}},"alternative-id":["10.1002\/advs.202205993"],"URL":"https:\/\/doi.org\/10.1002\/advs.202205993","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,17]]},"assertion":[{"value":"2022-10-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-04-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2205993"}}