title: Druggable sensors of the unfolded protein response.
abstract: The inability of cells to properly fold, modify and assemble secretory and transmembrane proteins leads to accumulation of misfolded proteins in the endoplasmic reticulum (ER). Under these conditions of 'ER stress', cell survival depends on homeostatic benefits from an intracellular signaling pathway called the unfolded protein response (UPR). When activated, the UPR induces transcriptional and translational programs that restore ER homeostasis. However, under high-level or chronic ER stress, these adaptive changes ultimately become overshadowed by alternative 'terminal UPR' signals that actively commit cells to degeneration, culminating in programmed cell death. Chronic ER stress and maladaptive UPR signaling are implicated in the etiology and pathogenesis of myriad human diseases. Naturally, this has generated widespread interest in targeting key nodal components of the UPR as therapeutic strategies. Here we summarize the state of this field with emphasis placed on two of the master UPR regulators, PERK and IRE1, which are both capable of being drugged with small molecules.
authors.affiliation: Department of Chemistry, University of Washington, Seattle, Seattle, Washington, USA.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Maly
authors.affiliation: 1] Department of Medicine, University of California-San Francisco, San Francisco, California, USA. [2] Diabetes Center, University of California-San Francisco, San Francisco, California, USA. [3] Lung Biology Center, University of California-San Francisco, San Francisco, California, USA. [4] California Institute for Quantitative Biosciences, University of California-San Francisco, San Francisco, California, USA.
authors.forename: Feroz R
authors.initials: FR
authors.lastname: Papa
mesh_terms: D000818:Animals; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D056811:Unfolded Protein Response / Q000187:drug effects*; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D004722:Endoribonucleases; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase