bims-unfpre 2024-03-17 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2024–03–17
eleven papers selected by
Susan Logue, University of Manitoba

Endoplasmic reticulum stress enhances the expression of TLR3-induced TSLP by airway epithelium.
Decoding contextual crosstalk: revealing distinct interactions between non-coding RNAs and unfolded protein response in breast cancer.
Inhibition of BRD4 Attenuates ER Stress-induced Renal Ischemic-Reperfusion Injury.
G protein-coupled receptor 84 gene expression is regulated by the ER stress response in the liver.
ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway.
Targeting eIF2α in TBI-induced traumatic optic neuropathy: Effects of Salubrinal and the Integrated Stress Response Inhibitor.
Arnicolide D induces endoplasmic reticulum stress-mediated oncosis via ATF4 and CHOP in hepatocellular carcinoma cells.
Cisplatin Nephrotoxicity Is Critically Mediated by the Availability of BECLIN1.
Benefits and Pitfalls of a Glycosylation Inhibitor Tunicamycin in the Therapeutic Implication of Cancers.
STING contributes to lipopolysaccharide-induced tubular cell inflammation and pyroptosis by activating endoplasmic reticulum stress in acute kidney injury.
Simultaneous proteome localization and turnover analysis reveals spatiotemporal features of protein homeostasis disruptions.

Am J Physiol Lung Cell Mol Physiol. 2024 Mar 12.

Endoplasmic reticulum stress enhances the expression of TLR3-induced TSLP by airway epithelium.

Prabuddha S Pathinayake, Alan C-Y Hsu, Kristy S Nichol, Jay C Horvat, Philip M Hansbro, Peter A Wark.

  Thymic stromal lymphopoietin (TSLP) is an epithelial-derived pleiotropic cytokine that regulates T-helper 2 (Th2) immune responses in the lung and plays a major role in severe uncontrolled asthma. Emerging evidence suggests a role for endoplasmic reticulum (ER) stress in the pathogenesis of asthma. In this study, we determined if ER stress and the unfolded protein response (UPR) signalling are involved in TSLP induction in the airway epithelium. For this, we treated human bronchial epithelial basal cells and differentiated primary bronchial epithelial cells with ER stress inducers and the TSLP mRNA and protein expression was determined. A series of siRNA gene knockdown experiments were conducted to determine the ER stress-induced TSLP signalling pathways. cDNA collected from asthmatic bronchial biopsies was used to determine the gene correlation between ER stress and TSLP. Our results show that ER stress signalling induces TSLP mRNA expression via the PERK-CHOP signalling pathway. AP-1 transcription factor is important in regulating this ER stress-induced TSLP mRNA induction, though ER stress alone cannot induce TSLP protein production. However, ER stress significantly enhances TLR3-induced TSLP protein secretion in the airway epithelium. TSLP and ER stress (PERK) mRNA expression positively correlates in bronchial biopsies from participants with asthma, particularly in neutrophilic asthma. In conclusion, these results suggest that ER stress primes TSLP which is then enhanced further upon TLR3 activation, which may induce severe asthma exacerbations. Targeting ER stress using pharmacological interventions may provide novel therapeutics for severe uncontrolled asthma.

Keywords:  ER Stress; Severe Neutrophilic asthma; TSLP; Unfolded Protein Response

DOI:  https://doi.org/10.1152/ajplung.00378.2023
Cancer Cell Int. 2024 Mar 11. 24(1): 104

Decoding contextual crosstalk: revealing distinct interactions between non-coding RNAs and unfolded protein response in breast cancer.

Negin Karamali, Arshia Daraei, Arman Rostamlou, Roya Mahdavi, Zahra Akbari Jonoush, Nooshin Ghadiri, Zahra Mahmoudi, Amirhossein Mardi, Moslem Javidan, Sepideh Sohrabi, Behzad Baradaran.

  Breast cancer is significantly influenced by endoplasmic reticulum (ER) stress, impacting both its initiation and progression. When cells experience an accumulation of misfolded or unfolded proteins, they activate the unfolded protein response (UPR) to restore cellular balance. In breast cancer, the UPR is frequently triggered due to challenging conditions within tumors. The UPR has a dual impact on breast cancer. On one hand, it can contribute to tumor growth by enhancing cell survival and resistance to programmed cell death in unfavorable environments. On the other hand, prolonged and severe ER stress can trigger cell death mechanisms, limiting tumor progression. Furthermore, ER stress has been linked to the regulation of non-coding RNAs (ncRNAs) in breast cancer cells. These ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play essential roles in cancer development by influencing gene expression and cellular processes. An improved understanding of how ER stress and ncRNAs interact in breast cancer can potentially lead to new treatment approaches. Modifying specific ncRNAs involved in the ER stress response might interfere with cancer cell survival and induce cell death. Additionally, focusing on UPR-associated proteins that interact with ncRNAs could offer novel therapeutic possibilities. Therefore, this review provides a concise overview of the interconnection between ER stress and ncRNAs in breast cancer, elucidating the nuanced effects of the UPR on cell fate and emphasizing the regulatory roles of ncRNAs in breast cancer progression.

Keywords:  Breast cancer; ER stress; Non-coding RNAs; Therapy; UPR

DOI:  https://doi.org/10.1186/s12935-024-03296-3
Int J Biol Sci. 2024 ;20(5): 1547-1562

Inhibition of BRD4 Attenuates ER Stress-induced Renal Ischemic-Reperfusion Injury.

Paula Diaz-Bulnes, Ramon M Rodríguez, Elisenda Banon-Maneus, María Laura Saiz, Cristian Ruiz Bernet, Viviana Corte-Iglesias, Maria Jose Ramirez-Bajo, Marta Lazo-Rodriguez, Isaac Tamargo-Gómez, Raúl R Rodrigues-Diez, Ana B Sanz, Carmen Diaz-Corte, Marta Ruiz-Ortega, Fritz Diekmann, Ana M Aransay, Carlos Lopez-Larrea, Beatriz Suarez-Alvarez.

  Renal ischemia-reperfusion injury (IRI) leads to endoplasmic reticulum (ER) stress, thereby initiating the unfolded protein response (UPR). When sustained, this response may trigger the inflammation and tubular cell death that acts to aggravate the damage. Here, we show that knockdown of the BET epigenetic reader BRD4 reduces the expression of ATF4 and XBP1 transcription factors under ER stress activation. BRD4 is recruited to the promoter of these highly acetylated genes, initiating gene transcription. Administration of the BET protein inhibitor, JQ1, one hour after renal damage induced by bilateral IRI, reveals reduced expression of ATF4 and XBP1 genes, low KIM-1 and NGAL levels and recovery of the serum creatinine and blood urea nitrogen levels. To determine the molecular pathways regulated by ATF4 and XBP1, we performed stable knockout of both transcription factors using CRISPR-Cas9 and RNA sequencing. The pathways triggered under ER stress were mainly XBP1-dependent, associated with an adaptive UPR, and partially regulated by JQ1. Meanwhile, treatment with JQ1 downmodulated most of the pathways regulated by ATF4 and related to the pathological processes during exacerbated UPR activation. Thus, BRD4 inhibition could be useful for curbing the maladaptive UPR activation mechanisms, thereby ameliorating the progression of renal disease.

Keywords:  BRD4; ER stress; Hypoxia; UPR; renal damage

DOI:  https://doi.org/10.7150/ijbs.83040
J Biochem. 2024 Mar 12. pii: mvae027. [Epub ahead of print]

G protein-coupled receptor 84 gene expression is regulated by the ER stress response in the liver.

Soshi Kanemoto.

  G protein-coupled receptor 84 (Gpr84) is reportedly activated by medium-chain fatty acids and is involved in the pathology of liver fibrosis. Inflammatory stimulants such as lipopolysaccharide and tumor necrosis factor-α upregulate Gpr84 expression. However, the detailed molecular mechanism by which Gpr84 is induced remains unknown. Inflammatory stimulation also evokes endoplasmic reticulum (ER) stress, but there has been no direct evidence to link Gpr84 expression and the ER stress response. Administration of tunicamycin (Tm) provokes ER stress and acute steatosis in the liver tissue of mice. Here, in situ hybridization analysis revealed that induction of Gpr84 expression occurred in parenchymal cells in the liver tissue following Tm administration. Gene expression analysis using a reporter assay showed that the intron 1 region of Gpr84 was involved in induction of the gene under ER stress conditions. Furthermore, Tm-dependent upregulation of Gpr84 was blocked by the small chemical compound AEBSF, an inhibitor of ER stress transducers, in vitro and in vivo. In conclusion, the current study marks the discovery that the ER stress agent Tm induces the expression of Gpr84.

Keywords:  Creb3 family; Endoplasmic reticulum stress; G protein-coupled receptor 84; Liver; Tunicamycin

DOI:  https://doi.org/10.1093/jb/mvae027
Int J Mol Sci. 2024 Feb 27. pii: 2768. [Epub ahead of print]25(5):

ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway.

Chang-Hoon Lim, Xue-Quan Fang, Hyeji Kang, Taerim Oh, Seonghoon Lee, Young-Seon Kim, Ji-Hong Lim.

  Ubiquitin-specific protease 7 inhibitors (USP7i) are considered a novel class of anticancer drugs. Cancer cells occasionally become insensitive to anticancer drugs, known as chemoresistance, by acquiring multidrug resistance, resulting in poor clinical outcomes in patients with cancer. However, the chemoresistance of cancer cells to USP7i (P22077 and P5091) and mechanisms to overcome it have not yet been investigated. In the present study, we generated human cancer cells with acquired resistance to USP7i-induced cell death. Gene expression profiling showed that heat stress response (HSR)- and unfolded protein response (UPR)-related genes were largely upregulated in USP7i-resistant cancer cells. Biochemical studies showed that USP7i induced the phosphorylation and activation of heat shock transcription factor 1 (HSF1), mediated by the endoplasmic reticulum (ER) stress protein kinase R-like ER kinase (PERK) signaling pathway. Inhibition of HSF1 and PERK significantly sensitized cancer cells to USP7i-induced cytotoxicity. Our study demonstrated that the ER stress-PERK axis is responsible for chemoresistance to USP7i, and inhibiting PERK is a potential strategy for improving the anticancer efficacy of USP7i.

Keywords:  chemoresistance; endoplasmic reticulum stress; heat shock transcription factor 1; ubiquitin-specific protease 7 inhibitor

DOI:  https://doi.org/10.3390/ijms25052768
bioRxiv. 2024 Feb 19. pii: 2024.02.15.580435. [Epub ahead of print]

Targeting eIF2α in TBI-induced traumatic optic neuropathy: Effects of Salubrinal and the Integrated Stress Response Inhibitor.

Shelby Hetzer, Rohan Bellary, Jordyn N Torrens, Robert F Grimaldi, Nathan K Evanson.

Traumatic brain injury (TBI) can induce traumatic axonal injury in the optic nerve, which is referred to as traumatic optic neuropathy (TON). TON occurs in up to 5% of TBI cases and leads to irreversible visual deficits. TON-induced phosphorylation of eIF2α, a downstream ER stress activator in the PERK pathway presents a potential point for therapeutic intervention. For eIF2α phosphorylation can lead to apoptosis or adaptation to stress. We hypothesized that dephosphorylation, rather than phosphorylation, of eIF2α would lead to reduced apoptosis and improved visual performance and retinal cell survival. Adult male mice were injected with Salubrinal (increases p-eIF2α) or ISRIB (decreases p-eIF2α) 60 minutes post-injury. Contrary to literature, both drugs hindered control animal visual function with minimal improvements in injured mice. Additionally, differences in eIF2α phosphorylation, antioxidant responses, and protein folding chaperones were different when examining protein expression between the retina and its axons in the optic nerve. These results reveal important compartmentalized ER stress responses to axon injury and suggest that interventions in the PERK pathway may alter necessary homeostatic regulation of the UPR in the retina.

DOI: https://doi.org/10.1101/2024.02.15.580435
Cell Death Discov. 2024 Mar 12. 10(1): 134

Arnicolide D induces endoplasmic reticulum stress-mediated oncosis via ATF4 and CHOP in hepatocellular carcinoma cells.

Yu-Shan Lin, Zhiwei Sun, Li-Sha Shen, Rui-Hong Gong, Jia-Wen Chen, Yanfeng Xu, Haiyang Yu, Sibao Chen, Guo-Qing Chen.

Endoplasmic reticulum (ER) stress can trigger various cell death mechanisms beyond apoptosis, providing promise in cancer treatment. Oncosis, characterized by cellular swelling and increased membrane permeability, represents a non-apoptotic form of cell death. In our study, we discovered that Arnicolide D (AD), a natural sesquiterpene lactone compound, induces ER stress-mediated oncosis in hepatocellular carcinoma (HCC) cells, and this process is reactive oxygen species (ROS)-dependent. Furthermore, we identified the activation of the PERK-eIF2α-ATF4-CHOP pathway during ER stress as a pivotal factor in AD-induced oncosis. Notably, the protein synthesis inhibitor cycloheximide (CHX) was found to effectively reverse AD-induced oncosis, suggesting ATF4 and CHOP may hold crucial roles in the induction of oncosis by AD. These proteins play a vital part in promoting protein synthesis during ER stress, ultimately leading to cell death. Subsequent studies, in where we individually or simultaneously knocked down ATF4 and CHOP in HCC cells, provided further confirmation of their indispensable roles in AD-induced oncosis. Moreover, additional animal experiments not only substantiated AD's ability to inhibit HCC tumor growth but also solidified the essential role of ER stress-mediated and ROS-dependent oncosis in AD's therapeutic potential. In summary, our research findings strongly indicate that AD holds promise as a therapeutic agent for HCC by its ability to induce oncosis.

DOI: https://doi.org/10.1038/s41420-024-01911-w
Int J Mol Sci. 2024 Feb 22. pii: 2560. [Epub ahead of print]25(5):

Cisplatin Nephrotoxicity Is Critically Mediated by the Availability of BECLIN1.

Tillmann Bork, Camila Hernando-Erhard, Wei Liang, Zhejia Tian, Kosuke Yamahara, Tobias B Huber.

  Cisplatin nephrotoxicity is a critical limitation of solid cancer treatment. Until now, the complex interplay of various pathophysiological mechanisms leading to proximal tubular cell apoptosis after cisplatin exposure has not been fully understood. In our study, we assessed the role of the autophagy-related protein BECLIN1 (ATG6) in cisplatin-induced acute renal injury (AKI)-a candidate protein involved in autophagy and with putative impact on apoptosis by harboring a B-cell lymphoma 2 (BCL2) interaction site of unknown significance. By using mice with heterozygous deletion of Becn1, we demonstrate that reduced intracellular content of BECLIN1 does not impact renal function or autophagy within 12 months. However, these mice were significantly sensitized towards cisplatin-induced AKI, and by using Becn1+/-;Sglt2-Cre;Tomato/EGFP mice with subsequent primary cell analysis, we confirmed that nephrotoxicity depends on proximal tubular BECLIN1 content. Mechanistically, BECLIN1 did not impact autophagy or primarily the apoptotic pathway. In fact, a lack of BECLIN1 sensitized mice towards cisplatin-induced ER stress. Accordingly, the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) blunted cisplatin-induced cell death in Becn1 heterozygosity. In conclusion, our data first highlight a novel role of BECLIN1 in protecting against cellular ER stress independent from autophagy. These novel findings open new therapeutic avenues to intervene in this important intracellular stress response pathway with a promising impact on future AKI management.

Keywords:  AKI; BECLIN1; ER stress; apoptosis; autophagy; cisplatin

DOI:  https://doi.org/10.3390/ijms25052560
Cells. 2024 Feb 25. pii: 395. [Epub ahead of print]13(5):

Benefits and Pitfalls of a Glycosylation Inhibitor Tunicamycin in the Therapeutic Implication of Cancers.

Snigdha Banerjee, Affan A Ansari, Sunil P Upadhyay, Daniel J Mettman, Jamie R Hibdon, Mohiuddin Quadir, Pratyusha Ghosh, Anjali Kambhampati, Sushanta K Banerjee.

  The aberrant glycosylation is a hallmark of cancer progression and chemoresistance. It is also an immune therapeutic target for various cancers. Tunicamycin (TM) is one of the potent nucleoside antibiotics and an inhibitor of aberrant glycosylation in various cancer cells, including breast cancer, gastric cancer, and pancreatic cancer, parallel with the inhibition of cancer cell growth and progression of tumors. Like chemotherapies such as doxorubicin (DOX), 5'fluorouracil, etoposide, and cisplatin, TM induces the unfolded protein response (UPR) by blocking aberrant glycosylation. Consequently, stress is induced in the endoplasmic reticulum (ER) that promotes apoptosis. TM can thus be considered a potent antitumor drug in various cancers and may promote chemosensitivity. However, its lack of cell-type-specific cytotoxicity impedes its anticancer efficacy. In this review, we focus on recent advances in our understanding of the benefits and pitfalls of TM therapies in various cancers, including breast, colon, and pancreatic cancers, and discuss the mechanisms identified by which TM functions. Finally, we discuss the potential use of nano-based drug delivery systems to overcome non-specific toxicity and enhance the therapeutic efficacy of TM as a targeted therapy.

Keywords:  breast cancer; drug resistance; glycosylation; immunotherapy; multidrug therapy; nanoparticle; tunicamycin

DOI:  https://doi.org/10.3390/cells13050395
Cell Death Dis. 2024 Mar 14. 15(3): 217

STING contributes to lipopolysaccharide-induced tubular cell inflammation and pyroptosis by activating endoplasmic reticulum stress in acute kidney injury.

Yun Cao, Xinghua Chen, Zijing Zhu, Zilv Luo, Yiqun Hao, Xueyan Yang, Jun Feng, Zongwei Zhang, Jijia Hu, Yonghong Jian, Jiefu Zhu, Wei Liang, Zhaowei Chen.

Recently, innate immunity and inflammation were recognized as the key factors for acute kidney injury (AKI) caused by sepsis, which is closely related to high mortality. Stimulator of interferon genes (STING) has emerged as a critical component of innate immune and inflammatory responses. However, the role of STING in the pathogenesis of septic AKI remains unclear. This study demonstrated that the STING was significantly activated in tubular cells induced by lipopolysaccharide (LPS) in vivo and in vitro. Tubule-specific STING knockout attenuated LPS-induced renal dysfunction and pathological changes. Mechanistically, the STING pathway promotes NOD-like receptor protein 3 (NLRP3) activation. STING triggers endoplasmic reticulum (ER) stress to induce mitochondrial reactive oxygen species (mtROS) overproduction, enhancing thioredoxin-interacting protein activation and association with NLRP3. Eventually, the NLRP3 inflammasome leads to tubular cell inflammation and pyroptosis. This study revealed the STING-regulated network and further identified the STING/ER stress/mtROS/NLRP3 inflammasome axis as an emerging pathway contributing to tubular damage in LPS-induced AKI. Hence, targeting STING may be a promising therapeutic strategy for preventing septic AKI.

DOI: https://doi.org/10.1038/s41419-024-06600-1
Nat Commun. 2024 Mar 11. 15(1): 2207

Simultaneous proteome localization and turnover analysis reveals spatiotemporal features of protein homeostasis disruptions.

Jordan Currie, Vyshnavi Manda, Sean K Robinson, Celine Lai, Vertica Agnihotri, Veronica Hidalgo, R W Ludwig, Kai Zhang, Jay Pavelka, Zhao V Wang, June-Wha Rhee, Maggie P Y Lam, Edward Lau.

The spatial and temporal distributions of proteins are critical to protein function, but cannot be directly assessed by measuring protein bundance. Here we describe a mass spectrometry-based proteomics strategy, Simultaneous Proteome Localization and Turnover (SPLAT), to measure concurrently protein turnover rates and subcellular localization in the same experiment. Applying the method, we find that unfolded protein response (UPR) has different effects on protein turnover dependent on their subcellular location in human AC16 cells, with proteome-wide slowdown but acceleration among stress response proteins in the ER and Golgi. In parallel, UPR triggers broad differential localization of proteins including RNA-binding proteins and amino acid transporters. Moreover, we observe newly synthesized proteins including EGFR that show a differential localization under stress than the existing protein pools, reminiscent of protein trafficking disruptions. We next applied SPLAT to an induced pluripotent stem cell derived cardiomyocyte (iPSC-CM) model of cancer drug cardiotoxicity upon treatment with the proteasome inhibitor carfilzomib. Paradoxically, carfilzomib has little effect on global average protein half-life, but may instead selectively disrupt sarcomere protein homeostasis. This study provides a view into the interactions of protein spatial and temporal dynamics and demonstrates a method to examine protein homeostasis regulations in stress and drug response.

DOI: https://doi.org/10.1038/s41467-024-46600-5