title: Proteostasis: bad news and good news from the endoplasmic reticulum.
abstract: The endoplasmic reticulum (ER) is an intracellular compartment dedicated to the synthesis and maturation of secretory and membrane proteins, totalling about 30% of the total eukaryotic cells proteome. The capacity to produce correctly folded polypeptides and to transport them to their correct intra- or extracellular destinations relies on proteostasis networks that regulate and balance the activity of protein folding, quality control, transport and degradation machineries. Nutrient and environmental changes, pathogen infection aging and, more relevant for the topics discussed in this review, mutations that impair attainment of the correct 3D structure of nascent polypeptide chains may compromise the activity of the proteostasis networks with devastating consequences on cells, organs and organisms' homeostasis. Here we present a review of mechanisms regulating folding and quality control of proteins expressed in the ER, and we describe the protein degradation and the ER stress pathways activated by the expression of misfolded proteins in the ER lumen. Finally, we highlight select examples of proteopathies (also known as conformational disorders or protein misfolding diseases) caused by protein misfolding in the ER and/or affecting cellular proteostasis and therapeutic interventions that might alleviate or cure the disease symptoms.
authors.affiliation: Institute for Research in Biomedicine, Protein Folding and Quality Control, Bellinzona, Switzerland.
authors.forename: Julia
authors.initials: J
authors.lastname: Noack
authors.affiliation: Institute for Research in Biomedicine, Protein Folding and Quality Control, Bellinzona, Switzerland.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Brambilla Pisoni
authors.affiliation: Institute for Research in Biomedicine, Protein Folding and Quality Control, Bellinzona, Switzerland; Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Switzerland.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Molinari
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism; D056947:Enzyme Replacement Therapy; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006467:Hemophilia A / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020140:Lysosomal Storage Diseases, Nervous System / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000627:therapeutic use; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D015398:Signal Transduction; D056811:Unfolded Protein Response / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D004722:Endoribonucleases; D015852:Eukaryotic Initiation Factor-2; D018832:Molecular Chaperones; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C528229:ERN1 protein, human