Increased demand on the protein folding capacity of the endoplasmic reticulum (ER) engages an adaptive reaction known as the unfolded protein response (UPR). The UPR regulates protein translation and the expression of numerous target genes that contribute to restore ER homeostasis or induce apoptosis of irreversibly damaged cells. UPR signaling is highly regulated and dynamic and integrates information about the type, intensity, and duration of the stress stimuli, thereby determining cell fate. Recent advances highlight novel physiological outcomes of the UPR beyond specialized secretory cells, particularly in innate immunity, metabolism, and cell differentiation. Here we discuss studies on the fine-tuning of the UPR and its physiological role in diverse organs and diseases.

Adaptation to endoplasmic reticulum (ER) stress depends on the activation of the unfolded protein response (UPR) stress sensor inositol‐requiring enzyme 1α (IRE1α), which functions as an endoribonuclease that splices the mRNA of the transcription factor XBP‐1 (X‐box‐binding protein‐1). Through a global proteomic approach we identified the BCL‐2 family member PUMA as a novel IRE1α interactor. Immun oprecipitation experiments confirmed this interaction and further detected the association of IRE1α with BIM, another BH3‐only protein. BIM and PUMA double‐knockout cells failed to maintain sustained XBP‐1 mRNA splicing after prolonged ER stress, resulting in early inactivation. Mutation in the BH3 domain of BIM abrogated the physical interaction with IRE1α, inhibiting its effects on XBP‐1 mRNA splicing. Unexpectedly, this regulation required BCL‐2 and was antagonized by BAD or the BH3 domain mimetic ABT‐737. The modulation of IRE1α RNAse activity by BH3‐only proteins was recapitulated in a cell‐free system suggesting a direct regulation. Moreover, BH3‐only proteins controlled XBP‐1 mRNA splicing in vivo and affected the ER stress‐regulated secretion of antibodies by primary B cells. We conclude that a subset of BCL‐2 family members participates in a new UPR‐regulatory network, thus assuming apoptosis‐unrelated functions.

Both autophagy and apoptosis are tightly regulated processes playing a central role in tissue homeostasis. Bax inhibitor 1 (BI‐1) is a highly conserved protein with a dual role in apoptosis and endoplasmic reticulum (ER) stress signalling through the regulation of the ER stress sensor inositol requiring kinase 1 α (IRE1α). Here, we describe a novel function of BI‐1 in the modulation of autophagy. BI‐1‐deficient cells presented a faster and stronger induction of autophagy, increasing LC3 flux and autophagosome formation. These effects were associated with enhanced cell survival under nutrient deprivation. Repression of autophagy by BI‐1 was dependent on cJun‐N terminal kinase (JNK) and IRE1α expression, possibly due to a displacement of TNF‐receptor associated factor‐2 (TRAF2) from IRE1α. Targeting BI‐1 expression in flies altered autophagy fluxes and salivary gland degradation. BI‐1 deficiency increased flies survival under fasting conditions. Increased expression of autophagy indicators was observed in the liver and kidney of bi‐1‐deficient mice. In summary, we identify a novel function of BI‐1 in multicellular organisms, and suggest a critical role of BI‐1 as a stress integrator that modulates autophagy levels and other interconnected homeostatic processes.