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Amyloid beta (A\u03b2) is generated by sequential processing of APP in the Golgi apparatus and endosomes, and its toxicity leads to neuron dysfunction and neurodegeneration. APP is selectively shuttled between intracellular membrane compartments and ultimately transported into lysosomes. However, the mechanisms underlying APP sorting signals and lysosomal degradation are largely unclear. In this study, we show that the von Hippel\u2012Lindau (VHL) protein, a subunit of an E3 ligase, recognizes the cytoplasmic domain of APP and mediates its ubiquitination. VHL-mediated ubiquitination facilitates the sorting of membrane APP into intraluminal vesicles of multivesicular bodies (MVBs) and subsequent degradation in lysosomes. Therefore, the loss of VHL accelerates A\u03b2 plaque deposition and memory deficits in AD model mice. Our findings reveal the role of VHL in restricting AD pathogenesis through ubiquitination-dependent MVB sorting and lysosomal degradation of APP.<\/jats:p>","DOI":"10.1093\/jmcb\/mjaf033","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T12:05:41Z","timestamp":1758283541000},"source":"Crossref","is-referenced-by-count":0,"title":["APP ubiquitination by VHL protein is essential for MVB sorting and lysosomal degradation"],"prefix":"10.1093","volume":"17","author":[{"given":"Chunyan","family":"Shan","sequence":"first","affiliation":[{"name":"Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University , Beijing 100871 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rixu","family":"Cong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University , Beijing 100871 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangyu","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University , Beijing 100871 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanjun","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University , Beijing 100871 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yonglu","family":"Tian","sequence":"additional","affiliation":[{"name":"School of Psychological and Cognitive Sciences, Peking University , Beijing 100871 ,","place":["China"]},{"name":"IDG\/McGovern Institute for Brain Research, Peking University , Beijing 100871 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenyuan","family":"Cao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University , Beijing 100871 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi\u2019an Jiaotong University , Xi\u2019an 710061 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linqing","family":"Miao","sequence":"additional","affiliation":[{"name":"Beijing Advanced Innovation Center for Intelligent Robots and Systems, Beijing Institute of Technology , Beijing 100081 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junlin","family":"Teng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University , Beijing 100871 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ning","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience, Translational Medicine Institute, Health Science Center, Xi\u2019an Jiaotong University , Xi\u2019an 710061 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianguo","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University , Beijing 100871 ,","place":["China"]},{"name":"Center for Quantitative Biology, Peking University , Beijing 100871 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,10,7]]},"reference":[{"key":"2026031723115736600_bib1","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1038\/sj.onc.1202473","article-title":"Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity","volume":"18","author":"Blankenship","year":"1999","journal-title":"Oncogene"},{"key":"2026031723115736600_bib2","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3390\/cells7030022","article-title":"Receptor tyrosine kinase ubiquitination and de-ubiquitination in signal transduction and receptor trafficking","volume":"7","author":"Critchley","year":"2018","journal-title":"Cells"},{"key":"2026031723115736600_bib3","first-page":"2520","article-title":"ESCRTs regulate amyloid precursor protein sorting in multivesicular bodies and intracellular amyloid-\u03b2 accumulation","volume":"128","author":"Edgar","year":"2015","journal-title":"J. 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