Selenoprotein S is required for clearance of C99 through endoplasmic reticulum-associated degradation

Jun Ki Jang, Ki Jun Park, Jea Hwang Lee, Kwan Young Ko, Seong Man Kang, Ick Young Kim

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Amyloid beta precursor protein (APP) is normally cleaved by α-secretase, but can also be cleaved by β-secretase (BACE1) to produce C99 fragments in the endoplasmic reticulum (ER) membrane. C99 is subsequently cleaved to amyloid β (Aβ), the aggregation of which is known to cause Alzheimer's disease. Therefore, C99 removing is for preventing the disease. Selenoprotein S (SelS) is an ER membrane protein participating in endoplasmic reticulum-associated degradation (ERAD), one of the stages in resolving ER stress of misfolded proteins accumulated in the ER. ERAD has been postulated as one of the processes to degrade C99; however, it remains unclear if the degradation depends on SelS. In this study, we investigated the effect of SelS on C99 degradation. We observed that both SelS and C99 were colocalized in the membrane fraction of mouse neuroblastoma Neuro2a (N2a) cells. While the level of SelS was increased by ER stress, the level of C99 was decreased. However, despite the induction of ER stress, there was no change in the amount of C99 in SelS knock-down cells. The interaction of C99 with p97(VCP), an essential component of the ERAD complex, did not occur in SelS knock-down cells. The ubiquitination of C99 was decreased in SelS knock-down cells. We also found that the extracellular amount of Aβ1−42 was relatively higher in SelS knock-down cells than in control cells. These results suggest that SelS is required for C99 degradation through ERAD, resulting in inhibition of Aβ production.

Original languageEnglish
Pages (from-to)444-450
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume486
Issue number2
DOIs
Publication statusPublished - 2017 Apr 29

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Keywords

  • Alzheimer's disease
  • Amyloid β
  • C99
  • ERAD
  • Selenoprotein S

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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