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

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. 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)