SENP1 deficiency promotes ER stress-induced apoptosis by increasing XBP1 SUMOylation.

The transcription factor X box-binding protein 1 (XBP1) is a key component of the endoplasmic reticulum (ER) stress response. Recently, it has been reported that the spliced XBP1 (XBP1s), an activated XBP1 during ER stress, can be SUMOylated. Here, we identify Sentrin/SUMO-specific protease 1 (SENP1) as a specific de-SUMOylation protease for XBP1. SENP1 can increase the transcriptional activity of XBP1. In Senp1 (-/-) cells, the SUMOylated XBP1 is accumulated, and the expression of XBP1 target genes is downregulated in response to ER stress. Moreover, SENP1 deficiency significantly increases ER stress-induced apoptosis through accumulating XBP1 SUMOylation. These results reveal an essential function of SENP1 in ER stress response through regulating XBP1 SUMOylation.