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APP ubiquitination by VHL protein is essential for MVB sorting and lysosomal degradation

Chunyan Shan1, Rixu Cong1, Xiangyu Xu1

  • 1Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing 100871, China.

Journal of Molecular Cell Biology
|October 7, 2025
PubMed

Insights

The von Hippel-Lindau protein (VHL) targets amyloid precursor protein (APP) for degradation, reducing Alzheimer's disease (AD) pathology. Loss of VHL accelerates Aβ plaque deposition and memory deficits in AD mice.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Alzheimer's disease (AD) pathogenesis involves amyloid precursor protein (APP) and amyloid beta (Aβ) accumulation.
  • Mechanisms of APP sorting and lysosomal degradation are not fully understood.
  • APP is processed in the Golgi and endosomes, leading to toxic Aβ generation.

Purpose of the Study:

  • To investigate the role of the von Hippel-Lindau protein (VHL) in APP processing and degradation.
  • To elucidate the mechanisms by which VHL influences APP trafficking and lysosomal degradation.
  • To determine the impact of VHL on Alzheimer's disease pathology.

Main Methods:

  • Studied the interaction between VHL and the cytoplasmic domain of APP.
  • Investigated VHL-mediated ubiquitination of APP.
  • Examined the effect of VHL on APP sorting into multivesicular bodies (MVBs) and lysosomal degradation.
  • Utilized Alzheimer's disease model mice to assess the in vivo role of VHL.

Main Results:

  • VHL recognizes and ubiquitinates the cytoplasmic domain of APP.
  • VHL-mediated ubiquitination promotes APP sorting into intraluminal vesicles of MVBs.
  • This sorting facilitates lysosomal degradation of APP.
  • Loss of VHL accelerates Aβ plaque deposition and memory deficits in AD model mice.

Conclusions:

  • VHL plays a critical role in restricting Alzheimer's disease pathogenesis.
  • VHL facilitates APP degradation via ubiquitination-dependent MVB sorting and lysosomal pathways.
  • Targeting VHL may offer a therapeutic strategy for Alzheimer's disease.
Keywords:
MVB sortingamyloid precursor proteinlysosomal degradationubiquitinationvon Hippel–Lindau protein

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