bims-unfpre 2020-05-31 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2020–05–31
eight papers selected by
Susan Logue, University of Manitoba

Peptidomimetic-based identification of FDA approved compounds inhibiting IRE1 activity.
Mechanisms, regulation and functions of the unfolded protein response.
Fine tuning of the unfolded protein response by ISRIB improves neuronal survival in a model of amyotrophic lateral sclerosis.
Targeting the IRE1-XBP1 axis to overcome endocrine resistance in breast cancer: Opportunities and challenges.
Kuanoniamine C stimulates bortezomib-induced cell death via suppression of glucose-regulated protein 78 in osteosarcoma.
Modeling the Critical Activation of Chaperone Machinery in Protein Folding.
Crosstalk between ER stress, NLRP3 inflammasome, and inflammation.
The Redox Activity of Protein Disulfide Isomerase Inhibits ALS Phenotypes in Cellular and Zebrafish Models.

FEBS J. 2020 May 23.

Peptidomimetic-based identification of FDA approved compounds inhibiting IRE1 activity.

Dimitrios Doultsinos, Antonio Carlesso, Chetan Chintha, James C Paton, Adrienne W Paton, Afshin Samali, Eric Chevet, Leif A Eriksson.

  Inositol Requiring Enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease that is a major mediator of the Unfolded Protein Response (UPR) during endoplasmic reticulum (ER) stress. Tumour cells experience ER stress due to adverse environmental cues such as hypoxia or nutrient shortage and high metabolic/protein folding demand. To cope with those stresses, cancer cells utilise IRE1 signalling as an adaptive mechanism. Here we report the discovery of the FDA approved compounds methotrexate, cefoperazone, folinic acid and fludarabine phosphate as IRE1 inhibitors. These were identified through a structural exploration of the IRE1 kinase domain using IRE1 peptide fragment docking and further optimization and pharmacophore development. The inhibitors were verified to have an impact on IRE1 activity in vitro and were tested for their ability to sensitise human cell models of glioblastoma multiforme (GBM) to chemotherapy. We show that all molecules identified sensitise glioblastoma cells to the standard of care chemotherapy temozolomide (TMZ).

Keywords:  Endoplasmic Reticulum; IRE1; Inhibitors; Unfolded Protein Response; glioblastoma

DOI:  https://doi.org/10.1111/febs.15372
Nat Rev Mol Cell Biol. 2020 May 26.

Mechanisms, regulation and functions of the unfolded protein response.

Claudio Hetz, Kezhong Zhang, Randal J Kaufman.

Cellular stress induced by the abnormal accumulation of unfolded or misfolded proteins at the endoplasmic reticulum (ER) is emerging as a possible driver of human diseases, including cancer, diabetes, obesity and neurodegeneration. ER proteostasis surveillance is mediated by the unfolded protein response (UPR), a signal transduction pathway that senses the fidelity of protein folding in the ER lumen. The UPR transmits information about protein folding status to the nucleus and cytosol to adjust the protein folding capacity of the cell or, in the event of chronic damage, induce apoptotic cell death. Recent advances in the understanding of the regulation of UPR signalling and its implications in the pathophysiology of disease might open new therapeutic avenues.

DOI: https://doi.org/10.1038/s41580-020-0250-z
Cell Death Dis. 2020 May 26. 11(5): 397

Fine tuning of the unfolded protein response by ISRIB improves neuronal survival in a model of amyotrophic lateral sclerosis.

Ricardo Bugallo, Elías Marlin, Ana Baltanás, Estefanía Toledo, Roberto Ferrero, Rodrigo Vinueza-Gavilanes, Laura Larrea, Montserrat Arrasate, Tomás Aragón.

Loss of protein folding homeostasis features many of the most prevalent neurodegenerative disorders. As coping mechanism to folding stress within the endoplasmic reticulum (ER), the unfolded protein response (UPR) comprises a set of signaling mechanisms that initiate a gene expression program to restore proteostasis, or when stress is chronic or overwhelming promote neuronal death. This fate-defining capacity of the UPR has been proposed to play a key role in amyotrophic lateral sclerosis (ALS). However, the several genetic or pharmacological attempts to explore the therapeutic potential of UPR modulation have produced conflicting observations. In order to establish the precise relationship between UPR signaling and neuronal death in ALS, we have developed a neuronal model where the toxicity of a familial ALS-causing allele (mutant G93A SOD1) and UPR activation can be longitudinally monitored in single neurons over the process of neurodegeneration by automated microscopy. Using fluorescent UPR reporters we established the temporal and causal relationship between UPR and neuronal death by Cox regression models. Pharmacological inhibition of discrete UPR processes allowed us to establish the contribution of PERK (PKR-like ER kinase) and IRE1 (inositol-requiring enzyme-1) mechanisms to neuronal fate. Importantly, inhibition of PERK signaling with its downstream inhibitor ISRIB, but not with the direct PERK kinase inhibitor GSK2606414, significantly enhanced the survival of G93A SOD1-expressing neurons. Characterization of the inhibitory properties of both drugs under ER stress revealed that in neurons (but not in glial cells) ISRIB overruled only part of the translational program imposed by PERK, relieving the general inhibition of translation, but maintaining the privileged translation of ATF4 (activating transcription factor 4) messenger RNA. Surprisingly, the fine-tuning of the PERK output in G93A SOD1-expressing neurons led to a reduction of IRE1-dependent signaling. Together, our findings identify ISRIB-mediated translational reprogramming as a new potential ALS therapy.

DOI: https://doi.org/10.1038/s41419-020-2601-2
Cancer Lett. 2020 May 21. pii: S0304-3835(20)30283-4. [Epub ahead of print]

Targeting the IRE1-XBP1 axis to overcome endocrine resistance in breast cancer: Opportunities and challenges.

David Barua, Ananya Gupta, Sanjeev Gupta.

  Estrogen receptor 1 (ESR1, which encodes estrogen receptor-alpha) is a key driver gene for the initiation and progression of hormone receptor-positive breast cancer. Estrogen receptor-alpha (ER) is expressed in up to 70% of cases, and patients are routinely treated with endocrine therapies. However, the development of resistance over time is common and occurs in one-third of ER-positive breast tumors, leading to disease progression and death. X-box binding protein 1 (XBP1), a key component of the unfolded protein response (UPR) and ER signaling pathway, generates a positive feedback regulatory loop that leads to increased expression of XBP1 and ER in luminal breast cancer. In this review, we highlight new insights into the mechanisms of crosstalk between XBP1 and ER signaling and its clinical implications. Next, we describe the key signaling nodes that play an important role in XBP1-mediated endocrine resistance in breast cancer. Further, we discuss XBP1 gene mutations in breast cancer and the role of these mutations in the emergence of endocrine resistance and response to treatment. Finally, we discuss the current state and future directions for targeting XBP1 in combination with standard endocrine therapy to improve clinical outcomes in endocrine-resistant breast cancer patients.

Keywords:  Breast cancer; ESR1 mutations; Endocrine resistance; Unfolded protein response; XBP1

DOI:  https://doi.org/10.1016/j.canlet.2020.05.020
Biochem Biophys Res Commun. 2020 Jun 18. pii: S0006-291X(20)30849-4. [Epub ahead of print]527(1): 289-296

Kuanoniamine C stimulates bortezomib-induced cell death via suppression of glucose-regulated protein 78 in osteosarcoma.

Kayo Machihara, Takushi Namba.

  Osteosarcoma is the most frequent and intractable malignancy of the bone in children and young adults. Surgical operation requires extensive excision of the cancer tissue and neighboring normal tissues. In addition, anticancer drugs and radiation therapy are thought to be almost ineffective. Glucose-regulated protein 78 (GRP78), a cell-protective endoplasmic reticulum (ER) chaperone protein, is one of the most promising anticancer targets for osteosarcoma. Here, by analyzing the molecular mechanisms of kuanoniamine C, we report that kuanoniamine C suppresses GRP78 expression via GRP78 mRNA degradation in an ER stress response-independent manner. Interestingly, kuanoniamine C-induced cell death and downregulation of GRP78 expression was regulated by p53 signaling. Moreover, co-treatment with bortezomib, which is a newly identified anticancer drug for osteosarcoma, and kuanoniamine C suppressed GRP78 protein expression, which is essential for the stimulation of bortezomib-induced cell death. These results suggest that co-treatment with bortezomib and kuanoniamine C is a novel therapeutic strategy for the treatment of osteosarcoma that enhances bortezomib-dependent cell death by the downregulation of GRP78, and this combination selectively targets the major cell population of osteosarcoma, which expresses wild-type p53.

Keywords:  GRP78; Kuanoniamine C; Osteosarcoma

DOI:  https://doi.org/10.1016/j.bbrc.2020.04.109
Adv Exp Med Biol. 2020 ;1194 351-358

Modeling the Critical Activation of Chaperone Machinery in Protein Folding.

Georgia Theocharopoulou, Panayiotis Vlamos.

  Protein homeostasis is a dynamic network that plays a pivotal role in systems' maintenance within a cell. This quality control system involves a number of mechanisms regarding the process of protein folding. Chaperones play a critical role in the folding, refolding, and unfolding of proteins. Aggregation of misfolded proteins is a common characteristic of neurodegenerative diseases. Chaperones act in a variety of pathways in this critical interplay between protein homeostasis network and misfolded protein's load. Moreover, ER stress-induced cell death mechanisms (such as the unfolded protein response) are activated as a response. Therefore, there is a critical balance in the accumulation of misfolded proteins and ER stress response mechanisms which can lead to cell death. Our focus is in understanding the different mechanisms that govern ER stress signaling in health and disease in order to represent the regulation of protein homeostasis and balance of protein synthesis and degradation in the ER. Our proposed model describes, using hybrid modeling, the function of chaperones' machinery for protein folding.

Keywords:  Chaperones; Misfolded proteins; Neurodegenerative diseases; Protein homeostasis; Quality control

DOI:  https://doi.org/10.1007/978-3-030-32622-7_33
Appl Microbiol Biotechnol. 2020 May 24.

Crosstalk between ER stress, NLRP3 inflammasome, and inflammation.

Wei Li, Ting Cao, Chunyi Luo, Jialun Cai, Xiangping Zhou, Xinhua Xiao, Shuangquan Liu.

  Endoplasmic reticulum stress (ERS) is a protective response to restore protein homeostasis by activating the unfolded protein response (UPR). However, UPR can trigger cell death under severe and/or persistently high ERS. The NLRP3 inflammasome is a complex of multiple proteins that activates the secretion of the proinflammatory cytokine IL-1β in a caspase-1-dependent manner to participate in the regulation of inflammation. The NLRP3 inflammasome involvement in ERS-induced inflammation has not been completely described. The intersection of ERS with multiple inflammatory pathways can initiate and aggravate chronic diseases. Accumulating evidence suggests that ERS-induced activation of NLRP3 inflammasome is the pathological basis of various inflammatory diseases. In this review, we have discussed the networks between ERS and NLRP3 inflammasome, with the view to identifying novel therapeutic targets in inflammatory diseases. KEY POINTS: • Endoplasmic reticulum stress (ERS) is an important factor for the activation of the NLRP3 inflammasomes that results in pathological processes. • ERS can activate the NLRP3 inflammasome to induce inflammatory responses via oxidative stress, calcium homeostasis, and NF-κB activation. • The interactions between ERS and NLRP3 inflammasome are associated with inflammation, which represent a potential therapeutic opportunity of inflammatory diseases.

Keywords:  Endoplasmic reticulum stress; Inflammation; NF-κB; NLRP3 inflammasome; Reactive oxygen species

DOI:  https://doi.org/10.1007/s00253-020-10614-y
iScience. 2020 May 22. pii: S2589-0042(20)30282-0. [Epub ahead of print]23(5): 101097

The Redox Activity of Protein Disulfide Isomerase Inhibits ALS Phenotypes in Cellular and Zebrafish Models.

Sonam Parakh, Sina Shadfar, Emma R Perri, Audrey M G Ragagnin, Claudia V Piattoni, Mariela B Fogolín, Kristy C Yuan, Hamideh Shahheydari, Emily K Don, Collen J Thomas, Yuning Hong, Marcelo A Comini, Angela S Laird, Damian M Spencer, Julie D Atkin.

  Pathological forms of TAR DNA-binding protein 43 (TDP-43) are present in almost all cases of amyotrophic lateral sclerosis (ALS), and 20% of familial ALS cases are due to mutations in superoxide dismutase 1 (SOD1). Redox regulation is critical to maintain cellular homeostasis, although how this relates to ALS is unclear. Here, we demonstrate that the redox function of protein disulfide isomerase (PDI) is protective against protein misfolding, cytoplasmic mislocalization of TDP-43, ER stress, ER-Golgi transport dysfunction, and apoptosis in neuronal cells expressing mutant TDP-43 or SOD1, and motor impairment in zebrafish expressing mutant SOD1. Moreover, previously described PDI mutants present in patients with ALS (D292N, R300H) lack redox activity and were not protective against ALS phenotypes. Hence, these findings implicate the redox activity of PDI centrally in ALS, linking it to multiple cellular processes. They also imply that therapeutics based on PDI's redox activity will be beneficial in ALS.

Keywords:  Molecular Biology; Neurogenetics; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2020.101097