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Small Molecules to Improve ER Proteostasis in Disease

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Small Molecules to Improve ER Proteostasis in Disease TIPS 1630 No. of Pages 12 Trends in Pharmacological Sciences Review Small Molecules to Improve ER Proteostasis in Disease Vicente Gonzalez-Teuber,1,2,3,8 Hector Albert-Gasco,4,8 Vincent C. Auyeung,5,6,8 Feroz R. Papa,5,* Giovanna R. Mallucci,4,* and Claudio Hetz1,2,3,7,* Abnormally high levels of misfolded proteins in the endoplasmic reticulum (ER) Highlights lumen result in a stress state that contributes to the progression of several patho- ER stress induces a cellular reaction, the logical conditions including diabetes, cancer, neurodegeneration, and immune UPR, to restore cellular proteostasis. dysregulation. ER stress triggers a dynamic signaling pathway known as the Chronic ER stress is a hallmark in the unfolded protein response (UPR). The UPR enforces adaptive or cell death pro- pathology of several human diseases grams by integrating information about the intensity and duration of the stress including cancer, obesity, neurodegen- stimuli. Thus, depending on the disease context, ER stress signaling can be eration, and diabetes. beneficial or detrimental. We discuss current efforts to develop small molecules Small molecules to target UPR media- to target distinct components of the UPR, and their possible applications in tors promise efficacy for the treatment treating human disease, focusing on neurodegenerative diseases, metabolic of many human diseases. disorders, and cancer. ER Proteostasis Control The function of a protein depends on its tertiary structure, a highly intricate 3D arrangement. Protein folding occurs for more than ten thousand different protein species in parallel [1],and one third of the proteome is folded and processed through the secretory pathway. This in- 1Biomedical Neuroscience Institute (BNI), volves additional challenges because proteins often contain several hydrophobic transmem- Faculty of Medicine, University of Chile, brane domains that tend to aggregate. The endoplasmic reticulum (ER) operates as a central Santiago, Chile 2Fondo de Financiamiento de Centros de site to execute folding and quality control of newly synthesized proteins. To assist protein fold- Investigación en Áreas Prioritarias ing, a plethora of foldases, oxidoreductases, and processing enzymes are expressed inside the (FONDAP) Center for Geroscience, Brain ER to maintain proteostasis (see Glossary) [2]. In addition, the folding process requires a Health, and Metabolism, Santiago, Chile 3Program of Cellular and Molecular tightly controlled redox and ionic environment. The folding capacity of the ER can be compro- Biology, Institute of Biomedical Science, mised under physiological and pathological circumstances, resulting in a cellular state known University of Chile, Santiago, Chile 4 as ER stress. To cope with protein folding stress, a signaling reaction has evolved to adjust UK Dementia Research Institute at the University of Cambridge and Department the protein folding demand according to needs in a dynamic manner, a pathway termed the of Clinical Neurosciences, University of unfolded protein response (UPR) (reviewed in [3]). Cambridge, Cambridge, UK 5Department of Medicine, Department of Pathology, Diabetes Center, Lung Biology The mammalian UPR is governed by three stress transducers located at the ER membrane that Center, and University of California San sense protein folding status. These signal transducers act in concert to integrate stress signals to Francisco (UCSF) Quantitative Bioscience enforce gene expression programs and cytosolic responses to restore proteostasis. In doing so, Institute, San Francisco, CA, USA 6Division of Pulmonary, Critical Care, and UPR activation increases the folding capacities of the ER, triggers ER and Golgi biogenesis and Sleep Medicine, Department of Medicine, protein degradation, and attenuates protein synthesis, among other reactions. If cells fail to University of California, San Francisco, adapt, the UPR leads to an apoptotic response, thus determining cell fate under chronic ER CA, USA 7Buck Institute for Research on Aging, stress (reviewed in [4,5]). Novato, CA, USA 8Equal contributions In the past decade ER stress and/or overactivation of UPR signaling have emerged as a prominent feature of several pathological conditions including diabetes mellitus, obesity, fibrosis, neurodegenerative diseases, ischemia, chronic inflammation, liver disease, and *Correspondence: [email protected] (F.R. Papa), cancer (reviewed in [6]).TheUPRhasbecomeanattractivetargetinthedesignof [email protected] (G.R. Mallucci), novel treatments, leading to the discovery of novel small molecules that can target spe- and [email protected] (C. Hetz). Trends in Pharmacological Sciences, Month 2019, Vol. xx, No. xx https://doi.org/10.1016/j.tips.2019.07.003 1 © 2019 Published by Elsevier Ltd. Trends in Pharmacological Sciences cific components of the pathway. In this article we discuss recent efforts to modulate Glossary the UPR using pharmacological approaches and their possible applications in disease Chaperone: proteins that assist protein treatment. folding, preventing their aggregation. ER-associated degradation (ERAD): a pathway which targets and eliminate UPR Signaling misfolded proteins of the endoplasmic Three main stress transducers initiate the UPR, including activating transcription factor 6 (ATF6 reticulum (ER) though ubiquitination, α and β isoforms), protein kinase RNA-like ER kinase (PERK), and inositol-requiring enzyme retrotranslocation to the cytosol, and degradation by the proteasome. (IRE1 α and β isoforms) (Figure 1) (reviewed in [4]). IRE1α isatypeItransmembraneER- ER stress: a condition where the resident protein, composed of an ER luminal sensor domain and, facing the cytoplasm, a ser- folding capacities of the ER are ine/threonine kinase domain and an RNase domain. Two models have been proposed to con- compromised, leading to the trol the initiation of the UPR (reviewed in [7]): an indirect model in which, under non-stress accumulation of abnormal levels of misfolded proteins. conditions, UPR sensors are repressed by binding to the ER chaperone BiP (also known as Integrated stress response (ISR): GRP78), which is released under ER stress. By contrast, a direct recognition model has stress signaling pathways that converge been proposed for IRE1α and PERK in which they bind to unfolded proteins as ligands to in- on the phosphorylation of eukaryotic α α duce their activation. IRE1 signaling involves its dimerization and trans-autophosphorylation, translation factor 2 (eIF2 ), decreasing global protein synthesis. leading to a conformational change that activates its RNase domain (Figure 2)(reviewedin Proteostasis: a cluster of biological [3]). Structural studies have demonstrated that the IRE1α kinase and RNase domains assem- pathways that control the biogenesis, ble into a back-to-back dimer and higher-order oligomers (Figure 2). IRE1α processes the folding, trafficking, and degradation of mRNA encoding the transcription factor X-box binding protein 1 (XBP1), excising a 26 nucleo- proteins at the cellular level. Internal ribosome entry sites – tide intron in the XBP1 mRNA, followed by exon exon ligation by the tRNA ligase RTCB [5]. (IRESs) and upstream open reading This unconventional splicing event shifts the coding reading frame, leading to the translation frames (uORFs): mRNA elements that of a potent transcription factor termed XBP1s [4]. XBP1s controls the transcription of genes in- enable mRNA translation in a 5′-cap- volved in lipid synthesis, protein folding, ER-associated degradation (ERAD), and protein independent manner. Unfolded protein response (UPR): a translocation into the ER, among other targets [5].IRE1α can also diversify the targets of its set of signaling reactions that are RNase activity through a process known as regulated IRE1-dependent decay (RIDD) (reviewed triggered by ER stress to restore in [8]). RIDD reduces the stability of ER-localized mRNAs, miRNAs, and rRNAs through cleav- proteostasis or induce the apoptosis of damaged cells. age of a specificsequence[9]. Although controversial, the ratio between RIDD and XBP1 mRNA splicing may depend on the oligomerization state of IRE1α [5].IRE1α can also act as a scaffold for signal transduction through the binding to adapter proteins and regulatory com- ponents, a platform referred to as the UPRosome [10].IRE1α-binding partners mediate the crosstalk with other signaling pathways, including JUN N-terminal kinase (JNK) and apoptosis signal-regulating kinase 1 (ASK1), nuclear factor κ light chain enhancer of activated B cells (NF- κB) (reviewed in [11]), and the cytoskeleton [12]. The intricacy of IRE1α activation affords mul- tiple opportunities to chemically modulate its various activities (reviewed in [13])(Box 1). PERK is also a type I transmembrane protein that contains a kinase domain in its cytosolic region. Under ER stress, PERK undergoes a conformational change allowing its dimerization and trans- autophosphorylation. Activated PERK phosphorylates the eukaryotic translation initiation fac- tor 2α (eIF2α). Phosphorylated eIF2α (P-eIF2α) binds tightly to eIF2B, preventing the forma- tion of the larger complex, thus inhibiting the initiation of translation, shutting down protein synthesis, and therefore reducing the load of proteins at the ER [14]. However, some mRNAs can overcome this suppression through non-canonical translation initiation by using an internal ribosome entry site (IRES) element or upstream open reading frames (uORFs). The best example of increased translation induced by eIF2α phosphorylation
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