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- W4366124549 endingPage "194936" @default.
- W4366124549 startingPage "194936" @default.
- W4366124549 abstract "Misfolded protein aggregation at both intracellular and extracellular milieus is thought to be the major etiology of Alzheimer's disease (AD). UBB+1, a frameshift variant of the ubiquitin B gene (UBB) results in a folded ubiquitin domain fused to a flexible unstructured extension. Accumulation of UBB+1 in extracellular plaques in the brains of AD patients undoubtedly suggests a role of the ubiquitin-proteasome system in AD. However, the exact mechanism of extracellular secretion of UBB+1 remains unknown. In an attempt to understand the molecular mechanism of UBB+1 secretion, we performed a survey of secretory pathways and identified the involvement of unconventional autophagosome-mediated UBB+1 secretion. Expression of UBB+1 was sufficient to stimulate LC3B/Atg8 conversion from LC3B-I to LC3B-II, which indicates initiation of the autophagy pathway. Furthermore, deficiency of ATG5 - a key player in autophagosome formation - inhibited UBB+1 secretion. Based on immunofluorescence 3D structured illumination (SIM) microscopy and co-immunoprecipitation, we provide evidence that UBB+1 is associated with the secretory autophagosome marker, SEC22B, while HSP90 possibly acts as a carrier. Using LC-MS/MS and mutagenesis we found that in cells, UBB+1 is ubiquitinated on lysine 11, 29, and 48, however, this ubiquitination does not contribute to its secretion. By contrast, proteasome or lysosome inhibition slightly enhanced secretion. Taken together, this study suggests that by ridding cells of UBB+1, secretory autophagosomes may alleviate the cellular stress associated with UBB+1, yet simultaneously mediate the spreading of a mutant specie with disordered characteristics to the extracellular milieu." @default.
- W4366124549 created "2023-04-19" @default.
- W4366124549 creator A5047898298 @default.
- W4366124549 creator A5069825701 @default.
- W4366124549 creator A5080516485 @default.
- W4366124549 date "2023-06-01" @default.
- W4366124549 modified "2023-10-03" @default.
- W4366124549 title "Alzheimer's disease-associated mutant ubiquitin (UBB+1) is secreted through an autophagosome-like vesicle-mediated unconventional pathway" @default.
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- W4366124549 doi "https://doi.org/10.1016/j.bbagrm.2023.194936" @default.
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