{
  "id": 18027155,
  "title": "APP functions at the endomembrane system",
  "url": "https://urgent.news/2026/11/03/app-functions-at-the-endomembrane-system",
  "topic": "tech",
  "section": "Tech",
  "published": "2026-11-03T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.11.01.763500v1?rss=1"
  },
  "original_language": "en",
  "account": "APP, a type I transmembrane protein, has been observed to interact with FE65, X11, and mDAB1 through the YENPTY motif in its intracellular domain. This interaction has been compared to the role of Notch in gene regulation. However, the specific mechanisms of APP's regulation of FE65 and their target genes remain unclear. To investigate this, APP695 was overexpressed in N2a cells, and APP was either deleted or mutated in H4 cells using CRISPR-Cas9. The effects of these modifications were analyzed through proteome comparison and immunoblotting, as well as immunofluorescence to examine the subcellular localizations of APP and FE65.\n\nThe study found that APP overexpression not only caused its retention in the Golgi apparatus and Endoplasmic reticulum but also induced FE65 clustering. This resulted in a significant reduction of ATF4 protein levels in N2a cells. Conversely, knocking down FE65 restored the ATF4 protein level. Furthermore, APP overexpression impeded autophagy, while the knockout of FE65 rescued LC3 conversion. It is noteworthy that the APP Swedish mutant did not affect ER stress or the autophagic flux but did facilitate the cleavage of APP-CTFs by gamma-secretase. The findings suggest that APP plays a crucial role in stabilizing the endomembrane system and the subcellular transport of FE65. More significantly, the regulation of autophagy by APP indicates that full-length APP could be a potential therapeutic target for delaying the onset of Alzheimer's disease.",
  "summary": "INTRODUCTION: APP is a type I transmembrane protein, and its intracellular domain (AICD) interacts with FE65, X11, and mDAB1, et al., through the YENPTY motif. Accordingly, it has been proposed that the functions of APP are similar to Notch, which regulates gene expression through releasing NICD after combining with its ligands. However, the detailed underlying mechanisms of how FE65 is regulated…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}