As the most conserved branch of the unfolded protein response (UPR), the inositol-requiring enzyme 1a (IRE1a)/X-box binding protein 1 (XBP1) pathway plays crucial roles in cell survival and cell death by upregulating UPR-associated genes involved in protein entry into the endoplasmic reticulum (ER) and ER-associated degradation (ERAD). Selenoprotein S (SelS) is localized to the ER membrane and involved in ERAD. Although SelS plays an important role in restoring ER stress, the SelS-dependent protective mechanisms against cell death remain unclear. Here, using an inducible SelS knockdown (KD) 313-L1 cell model, we showed that SelS KD resulted adipocyte death, which was associated with imbalance of the Bcl-2 family members. Furthermore, SelS KD decreased spliced XBPI (sXBP1), increased IRE1 alpha and p-JNK, suggesting a role of SeIS in the modulation of the IRE1 alpha-sXBP1 pathway. Moreover, adipocyte death induced by SelS suppression can be inhibited by overexpression of 5XBP1. Thus, it is proposed that SeIS promotes cell survival through the IRE1 alpha-XBP1 signaling pathway. (C) 2018 Published by Elsevier Inc.