bims-unfpre 2020-02-23 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2020–02–23
eight papers selected by
Susan Logue, University of Manitoba

Insights Into the Role of Endoplasmic Reticulum Stress in Infectious Diseases.
Endoplasmic reticulum stress signaling in cancer and neurodegenerative disorders: tools and strategies to understand its complexity.
Sestrin2 protects dendritic cells against endoplasmic reticulum stress-related apoptosis induced by high mobility group box-1 protein.
Targeting the Unfolded Protein Response in Hormone-Regulated Cancers.
Repression of viral gene expression and replication by the unfolded protein response effector XBP1u.
LncRNA LUCRC Regulates Colorectal Cancer Cell Growth and Tumorigenesis by Targeting Endoplasmic Reticulum Stress Response.
IRE1α-targeting downregulates ABC transporters and overcomes drug resistance of colon cancer cells.
Mitochondrial Unfolded Protein Response and Its Roles in Stem Cells.

Front Immunol. 2019 ;10 3147

Insights Into the Role of Endoplasmic Reticulum Stress in Infectious Diseases.

Ji-Ae Choi, Chang-Hwa Song.

  The endoplasmic reticulum (ER) is the major organelle in the cell for protein folding and plays an important role in cellular functions. The unfolded protein response (UPR) is activated in response to misfolded or unfolded protein accumulation in the ER. However, the UPR successfully alleviates the ER stress. If UPR fails to restore ER homeostasis, apoptosis is induced. ER stress plays an important role in innate immune signaling in response to microorganisms. Dysregulation of UPR signaling contributes to the pathogenesis of a variety of infectious diseases. In this review, we summarize the contribution of ER stress to the innate immune response to invading microorganisms and its role in the pathogenesis of infectious diseases.

Keywords:  ER stress; UPR (unfolded protein response); apoptosis; bacteria; infection; infectious disease; pathogen; viruses

DOI:  https://doi.org/10.3389/fimmu.2019.03147
Pharmacol Res. 2020 Feb 14. pii: S1043-6618(19)32852-X. [Epub ahead of print] 104702

Endoplasmic reticulum stress signaling in cancer and neurodegenerative disorders: tools and strategies to understand its complexity.

Daniela Correia da Silva, Patrícia Valentão, Paula B Andrade, David M Pereira.

  The endoplasmic reticulum (ER) comprises a network of tubules and vesicles that constitutes the largest organelle of the eukaryotic cell. Being the location where most proteins are synthesized and folded, it is crucial for the upkeep of cellular homeostasis. Disturbed ER homeostasis triggers the activation of a conserved molecular machinery, termed the unfolded protein response (UPR), that comprises three major signaling branches, initiated by the protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1) and the activating transcription factor 6 (ATF6). Given the impact of this intricate signaling network upon an extensive list of cellular processes, including protein turnover and autophagy, ER stress is involved in the onset and progression of multiple diseases, including cancer and neurodegenerative disorders. There is, for this reason, an increasing number of publications focused on characterizing and/or modulating ER stress, which have resulted in a wide array of techniques employed to study ER-related molecular events. This review aims to sum up the essentials on the current knowledge of the molecular biology of endoplasmic reticulum stress, while highlighting the available tools used in studies of this nature.

Keywords:  4-Phenylbutyric acid (PubChem CID: 4775); ATF6; DTT (PubChem CID: 446094); IRE-1; PERK; Thapsigargin (PubChem CID: 126969181); autophagy; brefeldin (PubChem CID: 5287620); endoplasmic reticulum stress; palmitic acid (PubChem CID: 985); salubrinal (PubChem CID: 5717801); tunicamycin (PubChem CID: 56927848); unfolded protein response

DOI:  https://doi.org/10.1016/j.phrs.2020.104702
Cell Death Dis. 2020 Feb 18. 11(2): 125

Sestrin2 protects dendritic cells against endoplasmic reticulum stress-related apoptosis induced by high mobility group box-1 protein.

Li-Xue Wang, Xiao-Mei Zhu, Yi-Nan Luo, Yao Wu, Ning Dong, Ya-Lin Tong, Yong-Ming Yao.

Sestrin2 (SESN2) is a highly evolutionary conserved protein and involved in different cellular responses to various stresses. However, the potential function of SESN2 in immune system remains unclear. The present study was designed to test whether dendritic cells (DCs) could express SESN2, and investigate the underlying molecular mechanism as well as its potential significance. Herein, we firstly reported that SESN2 was expressed in DCs after high mobility group box-1 protein (HMGB1) stimulation and the apoptosis of DCs was obviously increased when SESN2 gene silenced by siRNA. Cells undergone SESN2-knockdown promoted endoplasmic reticulum (ER) stress (ERS)-related cell death, markedly exacerbated ER disruption as well as the formation of dilated and aggregated structures, and they significantly aggravated the extent of ERS response. Conversely, overexpressing SESN2 DCs markedly decreased apoptotic rates and attenuated HMGB1-induced ER morphology fragment together with inhibition of ERS-related protein translation. Furthermore, sesn2-/--deficient mice manifested increased DC apoptosis and aggravated ERS extent in septic model. These results indicate that SESN2 appears to be a potential regulator to inhibit apoptotic ERS signaling that exerts a protective effect on apoptosis of DCs in the setting of septic challenge.

DOI: https://doi.org/10.1038/s41419-020-2324-4
Trends Cancer. 2020 Feb;pii: S2405-8033(19)30259-6. [Epub ahead of print]6(2): 160-171

Targeting the Unfolded Protein Response in Hormone-Regulated Cancers.

Yang Jin, Fahri Saatcioglu.

  Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One of these is the unfolded protein response (UPR), a highly conserved signaling pathway that is mounted in response to endoplasmic reticulum (ER) stress. Recent work showed that steroid hormones, in particular estrogens and androgens, regulate the canonical UPR pathways in breast cancer (BCa) and prostate cancer (PCa). In addition, UPR has pleiotropic effects in advanced disease and development of therapy resistance. These findings implicate the UPR pathway as a novel target in hormonally regulated cancers in the clinic. Here, we review the potential therapeutic value of recently developed small molecule inhibitors of UPR in hormone regulated cancers.

Keywords:  androgens; breast cancer; estrogens; prostate cancer; therapeutic targets; unfolded protein response

DOI:  https://doi.org/10.1016/j.trecan.2019.12.001
Elife. 2020 Feb 17. pii: e51804. [Epub ahead of print]9

Repression of viral gene expression and replication by the unfolded protein response effector XBP1u.

Florian Hinte, Eelco van Anken, Boaz Tirosh, Wolfram Brune.

  The unfolded protein response (UPR) is a cellular homeostatic circuit regulating protein synthesis and processing in the ER by three ER-to-nucleus signaling pathways. One pathway is triggered by the inositol-requiring enzyme 1 (IRE1), which splices the X-box binding protein 1 (Xbp1) mRNA, thereby enabling expression of XBP1s. Another UPR pathway activates the activating transcription factor 6 (ATF6). Here we show that murine cytomegalovirus (MCMV), a prototypic β-herpesvirus, harnesses the UPR to regulate its own life cycle. MCMV activates the IRE1-XBP1 pathway early post infection to relieve repression by XBP1u, the product of the unspliced Xbp1 mRNA. XBP1u inhibits viral gene expression and replication by blocking the activation of the viral major immediate-early promoter by XBP1s and ATF6. These findings reveal a redundant function of XBP1s and ATF6 as activators of the viral life cycle, and an unexpected role of XBP1u as a potent repressor of both XBP1s and ATF6-mediated activation.

Keywords:  cell biology; infectious disease; microbiology; mouse; viruses

DOI:  https://doi.org/10.7554/eLife.51804
Front Genet. 2019 ;10 1409

LncRNA LUCRC Regulates Colorectal Cancer Cell Growth and Tumorigenesis by Targeting Endoplasmic Reticulum Stress Response.

Guo-Hui Tang, Xue Chen, Jian-Cheng Ding, Jun Du, Xiao-Ting Lin, Lu Xia, Jia-Bian Lian, Feng Ye, Xiu-Sheng He, Wen Liu.

  Colorectal cancer (CRC) is the second most common cause of cancer-related death worldwide, and is well known for its strong invasiveness, rapid recurrence, and poor prognosis. Long non-coding RNAs (lncRNAs) have been shown to be involved in the development of various types of cancers, including colorectal cancer. Here, through transcriptomic analysis and functional screening, we reported that lncRNA LUCRC (LncRNA Upregulated in Colorectal Cancer) is highly expressed in colorectal tumor samples and is required for colorectal cancer cell proliferation, migration, and invasion in cultured cells and tumorigenesis in xenografts. LUCRC was found to regulate target gene expression of unfolded protein response (UPR) in endoplasmic reticulum (ER), such as BIP. The clinical significance of LUCRC is underscored by the specific presence of LUCRC in blood plasma of patients with colorectal cancers. These findings revealed a critical regulator of colorectal cancer development, which might serve as a therapeutic target in colorectal cancer.

Keywords:  cell growth; colorectal cancer; long non-coding RNA; therapeutic target; unfolded protein response

DOI:  https://doi.org/10.3389/fgene.2019.01409
Cancer Lett. 2020 Feb 12. pii: S0304-3835(20)30069-0. [Epub ahead of print]476 67-74

IRE1α-targeting downregulates ABC transporters and overcomes drug resistance of colon cancer cells.

Qiang Gao, Xiu-Xiu Li, Yi-Ming Xu, Jin-Zhao Zhang, Shi-di Rong, Yan-Qing Qin, Jing Fang.

  Drug resistance is a big problem in cancer treatment and one of the most prominent mechanisms underlain is overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, ABCC1 and ABCG2. Inhibition of ABC transporters is an important approach to overcome drug resistance. The inositol-requiring enzyme 1α (IRE1α), an arm of unfolded protein response (UPR), splices XBP1 mRNA to generate an active transcription factor XBP1s. UPR is implicated in drug resistance. However, the underlying mechanism is unclear. We found that the anticancer drugs such as 5-fluorouracil (5-FU) activated the IRE1α-XBP1 pathway to induce the expression of ABCB1, ABCC1 and ABCG2 in colon cancer cells. Inhibition of IRE1α RNase activity with small molecule 4μ8c suppressed the drug-induced expression of these ABC transporters and sensitized 5-FU-resistant colon cancer cells to drug treatment. In vivo xenograft assay indicates that administration of 4μ8C substantially enhanced the efficacy of 5-FU chemotherapy on 5-FU-resistant colon cancer cells. These results suggest that IRE1α-targeting might be a strategy to cope with drug resistance of colon cancer.

Keywords:  ABC transporter; Colon cancer; Drug resistance; IRE1α

DOI:  https://doi.org/10.1016/j.canlet.2020.02.007
Stem Cells Dev. 2020 Feb 19.

Mitochondrial Unfolded Protein Response and Its Roles in Stem Cells.

Gerong Shen, Wei Liu, Lvwan Xu, Linlin Wang.

The mitochondrial unfolded protein response (UPRmt) is a mitochondrial protein quality control mechanism that is involved in many pathophysiological activities and maintain cellular homeostasis. The UPRmt signaling pathway in both c. elegans and in mammals has gained much attention in recent years. Many studies have reported the general function of UPRmt, including the relationship between UPRmt and longevity, survival, apoptosis, innate immunity, cancer growth, and neurodegenerative diseases. Stem cells are capable of self-renewing and differentiating, thus playing an important role in maintaining tissue homeostasis and tissue regeneration. Although the role and regulation of UPRmt in somatic cells have been widely studied, the regulatory mechanism of UPRmt in stem cells is not fully known. Thus, in this article, the regulatory role of UPRmt in stem cell proliferation, cellular differentiation and aging is reviewed. This review aims to provide novel insights for UPRmt promoting stem cell rejuvenation and improving life span in mammals.

DOI: https://doi.org/10.1089/scd.2019.0278