Direct proteasome binding and subsequent degradation of unspliced XBP-1 prevent its intracellular aggregation

Ami Navon, Ariel Gatushkin, Lior Zelcbuch, Shimon Shteingart, Marganit Farago, Rivka Hadar, Boaz Tirosh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

The non-canonical splicing of XBP-1 mRNA is a hallmark of the mammalian unfolded protein response (UPR). The proteasomal degradation of unspliced XBP-1 (XBP-1u) facilitates the termination of the UPR. Thus, understanding the mechanism of XBP-1u degradation may allow control over UPR duration and intensity. We show that XBP-1u interacts with purified 20S proteasomes through its unstructured C-terminus, which leads to its degradation in a manner that autonomously opens the proteasome gate. In living cells, the C-terminus of XBP-1u accumulates in aggresome structures in the presence of proteasome inhibitors. We propose that direct proteasomal degradation of XBP-1u prevents its intracellular aggregation. Structured summary: MINT-7302217: XBP1-u (uniprotkb:P17861-1) binds (MI:0407) to Proteasome subunit alpha 7.2 (uniprotkb:O14818) by pull down (MI:0096). MINT-7302148: Vimentin (uniprotkb:P08670) and XBP1-u (uniprotkb:P17861-1) colocalize (MI:0403) by fluorescence microscopy (MI:0416). MINT-7302163: XBP1-u (uniprotkb:P17861-1) binds (MI:0407) to Proteasome subunit alpha 5 (uniprotkb:P28066) by pull down (MI:0096). MINT-7302186: XBP1-u (uniprotkb:P17861-1) binds (MI:0407) to Proteasome subunit alpha 6 (uniprotkb:P60900) by pull down (MI:0096).

Original languageAmerican English
Pages (from-to)67-73
Number of pages7
JournalFEBS Letters
Volume584
Issue number1
DOIs
StatePublished - 4 Jan 2010

Keywords

  • ER stress
  • In vitro degradation
  • Proteasome
  • Ubiquitin
  • Unfolded protein response
  • XBP-1

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