ER stress sensing mechanism: Putting off the brake on UPR transducers

Endoplasmic reticulum (ER) stress is a major contributor to cancer, metabolic disorders and neurodegenerative diseases. ER proteostasis maintenance is controlled by a dynamic signaling network known as the unfolded protein response (UPR). The mechanisms underlying the detection of a stressful condition at the ER are poorly understood and may involve the participation of ER chaperones and the direct recognition of misfolded proteins by specialized sensors. IRE1α is an ER-localized kinase and endoribonuclease that initiates the most conserved UPR signaling branch [1]. IRE1α catalyzes the unconventional splicing of the mRNA encoding the X-box binding protein 1 (XBP1), leading to the expression of an active transcription factor termed XBP1s. In addition, IRE1α regulates the stability of certain mRNAs and miRNAs through a process termed regulated IRE1αdependent decay (RIDD) [1]. Since ER stress is emerging as a driver of multiple human disorders, a complex network of regulatory checkpoints has evolved to tightly control its signaling behavior. We recently developed a systematic study to identify IRE1α binding partners and discovered a novel ER factor that is necessary for optimal Editorial: Autophagy and Cell Death