Alzheimer's disease-associated mutant ubiquitin (UBB+1) is secreted through an autophagosome-like vesicle-mediated unconventional pathway

Ajay R. Wagh, Prasad Sulakshane, Michael H. Glickman

Research output: Contribution to journalReview articlepeer-review

1 Scopus citations

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.

Original languageEnglish
Article number194936
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
Volume1866
Issue number2
DOIs
StatePublished - Jun 2023

Keywords

  • Autophagosome mediated secretion
  • Autophagy
  • HSP90
  • Lysosome
  • Mutant ubiquitin
  • Proteasome
  • SEC22B
  • UBB
  • Ubiquitination

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics

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