bims-unfpre 2022-07-31 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2022–07–31
eleven papers selected by
Susan Logue, University of Manitoba

XAF1 drives apoptotic switch of endoplasmic reticulum stress response through destabilization of GRP78 and CHIP.
Endoplasmic Reticulum Stress, Oxidative Stress, and Rheumatic Diseases.
Nanodrugs Manipulating Endoplasmic Reticulum Stress for Highly Effective Antitumor Therapy.
ARHGEF2/EDN1 pathway participates in ER stress-related drug resistance of hepatocellular carcinoma by promoting angiogenesis and malignant proliferation.
Identification of Endoplasmic Reticulum Stress-Related Subtypes, Infiltration Analysis of Tumor Microenvironment, and Construction of a Prognostic Model in Colorectal Cancer.
Endoplasmic Reticulum Stress and Reactive Oxygen Species in Plants.
The plant endoplasmic reticulum UPRome: A repository and pathway browser for genes involved in signaling networks linked to the endoplasmic reticulum.
Pro-Survival Factor EDEM3 Confers Therapy Resistance in Prostate Cancer.
ZAP isoforms regulate unfolded protein response and epithelial- mesenchymal transition.
Activation of the Mitochondrial Unfolded Protein Response: A New Therapeutic Target?
Mitochondrial proteostasis stress in muscle drives a long-range protective response to alleviate dietary obesity independently of ATF4.

Cell Death Dis. 2022 Jul 28. 13(7): 655

XAF1 drives apoptotic switch of endoplasmic reticulum stress response through destabilization of GRP78 and CHIP.

Kyung-Woo Lee, Hui-Ra Hong, Ji-Sun Lim, Kyung-Phil Ko, Min-Goo Lee, Sung-Gil Chi.

X-linked inhibitor of apoptosis-associated factor-1 (XAF1) is a stress-inducible tumor suppressor that is commonly inactivated in many human cancers. Despite accumulating evidence for the pro-apoptotic role for XAF1 under various stressful conditions, its involvement in endoplasmic reticulum (ER) stress response remains undefined. Here, we report that XAF1 increases cell sensitivity to ER stress and acts as a molecular switch in unfolded protein response (UPR)-mediated cell-fate decisions favoring apoptosis over adaptive autophagy. Mechanistically, XAF1 interacts with and destabilizes ER stress sensor GRP78 through the assembly of zinc finger protein 313 (ZNF313)-mediated destruction complex. Moreover, XAF1 expression is activated through PERK-Nrf2 signaling and destabilizes C-terminus of Hsc70-interacting protein (CHIP) ubiquitin E3 ligase, thereby blocking CHIP-mediated K63-linked ubiquitination and subsequent phosphorylation of inositol-required enzyme-1α (IRE1α) that is involved in in the adaptive ER stress response. In tumor xenograft assays, XAF1-/- tumors display substantially lower regression compared to XAF1+/+ tumors in response to cytotoxic dose of ER stress inducer. XAF1 and GRP78 expression show an inverse correlation in human cancer cell lines and primary breast carcinomas. Collectively this study uncovers an important role for XAF1 as a linchpin to govern the sensitivity to ER stress and the outcomes of UPR signaling, illuminating the mechanistic consequence of XAF1 inactivation in tumorigenesis.

DOI: https://doi.org/10.1038/s41419-022-05112-0
Antioxidants (Basel). 2022 Jun 29. pii: 1306. [Epub ahead of print]11(7):

Endoplasmic Reticulum Stress, Oxidative Stress, and Rheumatic Diseases.

Bruna Miglioranza Scavuzzi, Joseph Holoshitz.

   BACKGROUND: The endoplasmic reticulum (ER) is a multi-functional organelle responsible for cellular homeostasis, protein synthesis, folding and secretion. It has been increasingly recognized that the loss of ER homeostasis plays a central role in the development of autoimmune inflammatory disorders, such as rheumatic diseases. Purpose/Main contents: Here, we review current knowledge of the contribution of ER stress to the pathogenesis of rheumatic diseases, with a focus on rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We also review the interplay between protein folding and formation of reactive oxygen species (ROS), where ER stress induces oxidative stress (OS), which further aggravates the accumulation of misfolded proteins and oxidation, in a vicious cycle. Intervention studies targeting ER stress and oxidative stress in the context of rheumatic diseases are also reviewed.
CONCLUSIONS: Loss of ER homeostasis is a significant factor in the pathogeneses of RA and SLE. Targeting ER stress, unfolded protein response (UPR) pathways and oxidative stress in these diseases both in vitro and in animal models have shown promising results and deserve further investigation.

Keywords:  ER stress inhibit; antioxidants; endoplasmic reticulum stress; oxidative stress; rheumatic diseases

DOI:  https://doi.org/10.3390/antiox11071306
Front Pharmacol. 2022 ;13 949001

Nanodrugs Manipulating Endoplasmic Reticulum Stress for Highly Effective Antitumor Therapy.

Yuting Xiang, Min Liu, Yunrong Yang, Yubo Wang, Yige Qiu, Shiqi Tu, Yitian Jiang, Yayun Nan, Xiaojie Zhang, Qiong Huang.

  Cancer is one of the leading causes of death worldwide due to high morbidity and mortality. Many attempts and efforts have been devoted to fighting cancer. Owing to the significant role of the endoplasmic reticulum (ER) in cell function, inducing ER stress can be promising for cancer treatment. However, the sustained activation of cytoprotective unfolded protein response (UPR) presents a tremendous obstacle for drugs in inducing unsolved ER stress in tumor cells, especially small-molecule drugs with poor bioavailability. Therefore, many emerging nanodrugs inducing and amplifying ER stress have been developed for efficient cancer treatment. More importantly, the novel discovery of ER stress in immunogenic cell death (ICD) makes it possible to repurpose antitumor drugs for immunotherapy through nanodrug-based strategies amplifying ER stress. Therefore, this mini-review aims to provide a comprehensive summary of the latest developments of the strategies underlying nanodrugs in the treatment of cancer via manipulating ER stress. Meanwhile, the prospects of ER stress-inducing nanodrugs for cancer treatment are systematically discussed, which provide a sound platform for novel therapeutic insights and inspiration for the design of nanodrugs in treating cancer.

Keywords:  endoplasmic reticulum stress; immunogenic cell death; nanodrugs; photodynamic therapy; tumor

DOI:  https://doi.org/10.3389/fphar.2022.949001
Cell Death Dis. 2022 Jul 27. 13(7): 652

ARHGEF2/EDN1 pathway participates in ER stress-related drug resistance of hepatocellular carcinoma by promoting angiogenesis and malignant proliferation.

Yue Zhu, Weiwei Liu, Zishu Wang, Yanfei Wang, Chaisheng Tan, Zhipeng Pan, Anqi Wang, Jiatao Liu, Guoping Sun.

Endoplasmic reticulum (ER) stress is widely involved in the drug resistance of hepatocellular carcinoma (HCC), but the mechanism of ER stress-induced drug resistance involves multiple signaling pathways that cannot be fully explained. Exploring genes associated with ER stress could yield a novel therapeutic target for ER stress-induced drug resistance. By analyzing RNA-sequencing, ATAC-sequencing, and Chip-sequencing data of Tunicamycin (TM)-treated or untreated HCC cells, we found that Rho guanine nucleotide exchange factor 2 (ARHGEF2) is upregulated in HCC cells with ER stress. ARHGEF2 plays an active role in tumor malignant progression. Notwithstanding, no research has been done on the link between ER stress and ARHGEF2. The function of ARHGEF2 as a novel downstream effector of ER stress in the angiogenesis and treatment resistance of HCC was revealed in this work. ARHGEF2 overexpression was linked to malignant development and a poor prognosis in HCC. ER stress stimulates the expression of ARHGEF2 through upregulation of ZNF263. Elevated ARHGEF2 accelerates HCC angiogenesis via the EDN1 pathway, enhances HCC cell proliferation and tumor growth both in vitro and in vivo, and contributes to ER stress-related treatment resistance. HCC cell growth was more inhibited when ARHGEF2 knockdown was paired with targeted medicines. Collectively, we uncovered a previously hidden mechanism where ARHGEF2/EDN1 pathway promotes angiogenesis and participates in ER stress-related drug resistance in HCC.

DOI: https://doi.org/10.1038/s41419-022-05099-8
Cancers (Basel). 2022 Jul 08. pii: 3326. [Epub ahead of print]14(14):

Identification of Endoplasmic Reticulum Stress-Related Subtypes, Infiltration Analysis of Tumor Microenvironment, and Construction of a Prognostic Model in Colorectal Cancer.

Baike Liu, Xiaonan Yin, Guangfu Jiang, Yang Li, Zhiyuan Jiang, Liming Qiang, Na Chen, Yating Fan, Chaoyong Shen, Lei Dai, Yuan Yin, Bo Zhang.

  Recently, endoplasmic reticulum (ER) stress has been shown to influence tumor progression and immune cell function in the tumor microenvironment (TME). However, the underlying role of ER stress-related gene patterns in colorectal cancer (CRC) development remains unclear. We analyzed the ER stress-related gene patterns in 884 patients with CRC from the Gene Expression Omnibus database and evaluated the cell-infiltrating patterns in the TME. Two ER stress-related patterns were identified in patients with CRC that had distinct cell-infiltrating patterns in the TME and clinical characteristics. A risk score and nomogram based on 14 screened prognosis-correlated genes was built and validated to predict patient survival. Patients with a higher risk score were shown to have an unfavorable prognosis, and the risk score was associated with cell infiltration and drug sensitivity. Furthermore, spatial transcriptomics data were utilized to explore ER stress-related gene patterns in CRC tissues, and it was shown that ER stress phenotype involves in the formation of the immunosuppressive TME. This study demonstrated that ER stress-related gene patterns play a role in influencing the TME and predicting prognosis. These analyses of ER stress in the TME of CRC might deepen our understanding of CRC progression and immune escape and provide novel insights into therapeutic strategies.

Keywords:  ER stress; colorectal cancer; prognostic model; spatial transcriptomics; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers14143326
Antioxidants (Basel). 2022 Jun 24. pii: 1240. [Epub ahead of print]11(7):

Endoplasmic Reticulum Stress and Reactive Oxygen Species in Plants.

Jiajian Cao, Chunhua Wang, Ning Hao, Toru Fujiwara, Tao Wu.

  The endoplasmic reticulum (ER) is a key compartment responsible for protein processing and folding, and it also participates in many signal transduction and metabolic processes. Reactive oxygen species (ROS) are important signaling messengers involved in the redox equilibrium and stress response. A number of abiotic and biotic stresses can trigger the accumulation of unfolded or misfolded proteins and lead to ER stress. In recent years, a number of studies have reported that redox metabolism and ROS are closely related to ER stress. ER stress can benefit ROS generation and even cause oxidative burden in plants, finally leading to oxidative stress depending on the degree of ER stress. Moreover, ER stress activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated ROS signaling, increases antioxidant defense mechanisms, and alters the glutathione (GSH) redox state. Meanwhile, the accumulation of ROS plays a special role in inducing the ER stress response. Given these factors, plants have evolved a series of complex regulatory mechanisms to interact with ROS in response to ER stress. In this review, we summarize the perceptions and responses of plant ER stress and oxidative protein folding in the ER. In addition, we analyze the production and signaling of ROS under ER stress in detail in order to provide a theoretical basis for reducing ER stress to improve the crop survival rate in agricultural applications.

Keywords:  endoplasmic reticulum stress; plants; reactive oxygen species; redox homeostasis; redox stress

DOI:  https://doi.org/10.3390/antiox11071240
Plant Direct. 2022 Jul;6(7): e431

The plant endoplasmic reticulum UPRome: A repository and pathway browser for genes involved in signaling networks linked to the endoplasmic reticulum.

Venura Herath, Kaylee Connolly, Anna Roach, Ashish Ausekar, Tracy Persky, Jeanmarie Verchot.

  The endoplasmic reticulum (ER) houses sensors that respond to environmental stress and underly plants' adaptative responses. These sensors transduce signals that lead to changes in nuclear gene expression. The ER to nuclear signaling pathways are primarily attributed to the unfolded protein response (UPR) and are also integrated with a wide range of development, hormone, immune, and stress signaling pathways. Understanding the role of the UPR in signaling network mechanisms that associate with particular phenotypes is crucially important. While UPR-associated genes are the subject of ongoing investigations in a few model plant systems, most remain poorly annotated, hindering the identification of candidates across plant species. This open-source curated database provides a centralized resource of peer reviewed knowledge of ER to nuclear signaling pathways for the plant community. We provide a UPRome interactive viewer for users to navigate through the pathways and to access annotated information. The plant ER UPRome website is located at http://uprome.tamu.edu. We welcome contributions from the researchers studying the ER UPR to incorporate additional genes into the database through the "contact us" page.

Keywords:  curated database; plant protein interaction maps; plant signal transduction; unfolded protein response

DOI:  https://doi.org/10.1002/pld3.431
Int J Mol Sci. 2022 Jul 25. pii: 8184. [Epub ahead of print]23(15):

Pro-Survival Factor EDEM3 Confers Therapy Resistance in Prostate Cancer.

Emma Scott, Rebecca Garnham, Kathleen Cheung, Adam Duxfield, David J Elliott, Jennifer Munkley.

  Prostate cancer is the most common cancer in men, and it is primarily driven by androgen steroid hormones. The glycosylation enzyme EDEM3 is controlled by androgen signalling and is important for prostate cancer viability. EDEM3 is a mannosidase that trims mannose from mis-folded glycoproteins, tagging them for degradation through endoplasmic reticulum-associated degradation. Here, we find that EDEM3 is upregulated in prostate cancer, and this is linked to poorer disease-free survival. Depletion of EDEM3 from prostate cancer cells induces an ER stress transcriptomic signature, and EDEM3 overexpression is cyto-protective against ER stressors. EDEM3 expression also positively correlates with genes involved in the unfolded protein response in prostate cancer patients, and its expression can be induced through exposure to radiation. Importantly, the overexpression of EDEM3 promotes radio-resistance in prostate cancer cells and radio-resistance can be reduced through depletion of EDEM3. Our data thus implicate increased levels of EDEM3 with a role in prostate cancer pathology and reveal a new therapeutic opportunity to sensitise prostate tumours to radiotherapy.

Keywords:  EDEM; ER-stress; N-glycosylation; prostate cancer; radiotherapy

DOI:  https://doi.org/10.3390/ijms23158184
Proc Natl Acad Sci U S A. 2022 Aug 02. 119(31): e2121453119

ZAP isoforms regulate unfolded protein response and epithelial- mesenchymal transition.

Phuong Thao Ly, Shaohai Xu, Melissa Wirawan, Dahai Luo, Xavier Roca.

  Human ZAP inhibits many viruses, including HIV and coronaviruses, by binding to viral RNAs to promote their degradation and/or translation suppression. However, the regulatory role of ZAP in host mRNAs is largely unknown. Two major alternatively spliced ZAP isoforms, the constitutively expressed ZAPL and the infection-inducible ZAPS, play overlapping yet different antiviral and other roles that need further characterization. We found that the splicing factors hnRNPA1/A2, PTBP1/2, and U1-snRNP inhibit ZAPS production and demonstrated the feasibility to modulate the ZAPL/S balance by splice-switching antisense oligonucleotides in human cells. Transcriptomic analysis of ZAP-isoform-specific knockout cells revealed uncharacterized host mRNAs targeted by ZAPL/S with broad cellular functions such as unfolded protein response (UPR), epithelial-mesenchymal transition (EMT), and innate immunity. We established that endogenous ZAPL and ZAPS localize to membrane compartments and cytosol, respectively, and that the differential localization correlates with their target-RNA specificity. We showed that the ZAP isoforms regulated different UPR branches under resting and stress conditions and affected cell viability during ER stress. We also provided evidence for a different function of the ZAP isoforms in EMT-related cell migration, with effects that are cell-type dependent. Overall, this study demonstrates that the competition between splicing and IPA is a potential target for the modulation of the ZAPL/S balance, and reports new cellular transcripts and processes regulated by the ZAP isoforms.

Keywords:  alternative splicing; epithelial-mesenchymal transition; splice-switching antisense oligonucleotides; unfolded protein response; zinc finger antiviral protein

DOI:  https://doi.org/10.1073/pnas.2121453119
Biomedicines. 2022 Jul 06. pii: 1611. [Epub ahead of print]10(7):

Activation of the Mitochondrial Unfolded Protein Response: A New Therapeutic Target?

Juan M Suárez-Rivero, Carmen J Pastor-Maldonado, Suleva Povea-Cabello, Mónica Álvarez-Córdoba, Irene Villalón-García, Marta Talaverón-Rey, Alejandra Suárez-Carrillo, Manuel Munuera-Cabeza, Diana Reche-López, Paula Cilleros-Holgado, Rocío Piñero-Pérez, José A Sánchez-Alcázar.

  Mitochondrial dysfunction is a key hub that is common to many diseases. Mitochondria's role in energy production, calcium homeostasis, and ROS balance makes them essential for cell survival and fitness. However, there are no effective treatments for most mitochondrial and related diseases to this day. Therefore, new therapeutic approaches, such as activation of the mitochondrial unfolded protein response (UPRmt), are being examined. UPRmt englobes several compensation processes related to proteostasis and antioxidant mechanisms. UPRmt activation, through an hormetic response, promotes cell homeostasis and improves lifespan and disease conditions in biological models of neurodegenerative diseases, cardiopathies, and mitochondrial diseases. Although UPRmt activation is a promising therapeutic option for many conditions, its overactivation could lead to non-desired side effects, such as increased heteroplasmy of mitochondrial DNA mutations or cancer progression in oncologic patients. In this review, we present the most recent UPRmt activation therapeutic strategies, UPRmt's role in diseases, and its possible negative consequences in particular pathological conditions.

Keywords:  aging; heart diseases; homeostasis; lifespan; mitochondria; mitochondrial diseases; neurodegeneration; proteostasis; therapeutic target; unfolded protein response

DOI:  https://doi.org/10.3390/biomedicines10071611
Sci Adv. 2022 Jul 29. 8(30): eabo0340

Mitochondrial proteostasis stress in muscle drives a long-range protective response to alleviate dietary obesity independently of ATF4.

Qiqi Guo, Zhisheng Xu, Danxia Zhou, Tingting Fu, Wen Wang, Wanping Sun, Liwei Xiao, Lin Liu, Chenyun Ding, Yujing Yin, Zheng Zhou, Zongchao Sun, Yuangang Zhu, Wenjing Zhou, Yuhuan Jia, Jiachen Xue, Yuncong Chen, Xiao-Wei Chen, Hai-Long Piao, Bin Lu, Zhenji Gan.

Mitochondrial quality in skeletal muscle is crucial for maintaining energy homeostasis during metabolic stresses. However, how muscle mitochondrial quality is controlled and its physiological impacts remain unclear. Here, we demonstrate that mitoprotease LONP1 is essential for preserving muscle mitochondrial proteostasis and systemic metabolic homeostasis. Skeletal muscle-specific deletion of Lon protease homolog, mitochondrial (LONP1) impaired mitochondrial protein turnover, leading to muscle mitochondrial proteostasis stress. A benefit of this adaptive response was the complete resistance to diet-induced obesity. These favorable metabolic phenotypes were recapitulated in mice overexpressing LONP1 substrate ΔOTC in muscle mitochondria. Mechanistically, mitochondrial proteostasis imbalance elicits an unfolded protein response (UPRmt) in muscle that acts distally to modulate adipose tissue and liver metabolism. Unexpectedly, contrary to its previously proposed role, ATF4 is dispensable for the long-range protective response of skeletal muscle. Thus, these findings reveal a pivotal role of LONP1-dependent mitochondrial proteostasis in directing muscle UPRmt to regulate systemic metabolism.

DOI: https://doi.org/10.1126/sciadv.abo0340