The unfolded protein response and cell fate control

The secretory capacity of a cell is constantly challenged by physiological demands and pathological perturbations. To adjust and match the protein-folding capacity of the endoplasmic reticulum (ER) to changing secretory needs, cells employ a dynamic intracellular signaling pathway known as the unfolded protein response (UPR). Homeostatic activation of the UPR enforces adaptive programs that modulate and augment key aspects of the entire secretory pathway, whereas maladaptive UPR outputs trigger apoptosis. Here, we discuss recent advances into how the UPR integrates information about the intensity and duration of ER stress stimuli in order to control cell fate. These findings are timely and significant because they inform an evolving mechanistic understanding of a wide variety of human diseases, including diabetes mellitus, neuro-degeneration, and cancer, thus opening up the potential for new therapeuticmodalities to treat these diverse diseases.FONDECYT 1140549 FONDAP program 15150012 Millennium Institute P09-015-F European Commission RD MSCA-RISE 734749 Michael J. Fox Foundation for Parkinson's Research - Target Validation grant 9277 FONDEF ID16I10223 D11E1007 U.S. Office of Naval Research-Global (ONR-G) N62909-16-1-2003 U.S. Air Force Office of Scientific Research FA9550-16-1-0384 ALSRP Therapeutic Idea Award AL150111 Muscular Dystrophy Association 382453 CONICYT-Brazil 441921/2016-7 NIH RO1DK080955 RO1 DK100623 Burroughs Wellcome Fund Juvenile Diabetes Research Foundation (JDRF) 2-SRA-2016-234-S-N Breakthrough Therapeutics Initiative from Leona M. and Harry B. Helmsley Charitable Trus