bims-unfpre 2023-05-21 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2023‒05‒21
fifteen papers selected by
Susan Logue
University of Manitoba

The mTOR Signaling Pathway Interacts with the ER Stress Response and the Unfolded Protein Response in Cancer.
Linking the unfolded protein response to bioactive lipid metabolism and signalling in the cell non-autonomous extracellular communication of ER stress.
Chronic obstructive pulmonary disease and emerging ER stress-related therapeutic targets.
IRE1/XBP1 and endoplasmic reticulum signaling - from basic to translational research for cardiovascular disease.
The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB/PDIA1 contributing to liver damage and fibrosis.
Pseudophosphatase STYXL1 depletion enhances glucocerebrosidase trafficking to lysosomes via ER stress.
Endoplasmic reticulum stress impairs the immune regulation property of macrophages in asthmatic patients.
The RNA Demethylase ALKBH5 Maintains Endoplasmic Reticulum Homeostasis by Regulating UPR, Autophagy, and Mitochondrial Function.
Forsythiaside A alleviates Lipopolysacchrride-induced acute liver Injury through inhibiting endoplasmic reticulum stress and NLRP3 inflammasome activation.
GALECTIN-12 REGULATES IMMUNE RESPONSES IN THE SKIN THROUGH SEBACEOUS GLANDS.
Homeodomain-interacting protein kinase 2 regulates NLRP3 inflammasome activation through endoplasmic reticulum stress in septic liver injury.
Structure-Based Insight on the Mechanism of N-Glycosylation Inhibition by Tunicamycin.
Patient-Specific iPSC-Derived Models Link Aberrant Endoplasmic Reticulum Stress Sensing and Response to Juvenile Osteochondritis Dissecans Etiology.
Overexpression of VIRMA confers vulnerability to breast cancers via the m6A-dependent regulation of unfolded protein response.
UPR-induced ovarian cancer cell fusion: a mechanism favoring drug resistance?

Cancer Res. 2023 May 17. pii: CAN-22-3032. [Epub ahead of print]

The mTOR Signaling Pathway Interacts with the ER Stress Response and the Unfolded Protein Response in Cancer.

Sahar Mafi, Elham Ahmadi, Eileen Meehan, Conner Chiari, Behzad Mansoori, Hossein Sadeghi, Sahar Milani, Morteza Jafarinia, Shahram Taeb, Bayan Mafakheri Bashmagh, Seyed Mohammad Ali Mansoorian, Mohammad Sadegh Soltani-Zangbar, Kepeng Wang, Davoud Rostamzadeh.

The mTOR complex 1 (mTORC1) coordinates several important environmental and intracellular cues to control a variety of biological processes, such as cell growth, survival, autophagy, and metabolism in response to energy levels, growth signals, and nutrients. The endoplasmic reticulum (ER) is a crucial intracellular organelle that is essential for numerous cellular functions, including the synthesis, folding and modification of newly synthesized proteins, stress responsiveness, and maintainence of cellular homeostasis. mTOR-mediated upregulation of protein synthesis induces the accumulation of misfolded or unfolded proteins in the ER lumen which induces ER stress, leading to activation of the unfolded protein response (UPR) pathway. Reciprocally, ER stress regulates the PI3K/AKT/mTOR signaling pathway. Therefore, under pathological conditions, the crosstalk between the mTOR and UPR signaling pathways during cellular stress can critically affect cancer cell fate and may be involved in the pathogenesis and therapeutic outcome of cancer. Here, we discuss accumulating evidence showing the mechanism of action, interconnections, and molecular links between mTOR signaling and ER stress in tumorigenesis and highlight potential therapeutic implications for numerous cancers.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-3032
Bioessays. 2023 May 15. e2300029

Linking the unfolded protein response to bioactive lipid metabolism and signalling in the cell non-autonomous extracellular communication of ER stress.

Nicole T Watt, Anna McGrane, Lee D Roberts.

  The endoplasmic reticulum (ER) organelle is the key intracellular site of both protein and lipid biosynthesis. ER dysfunction, termed ER stress, can result in protein accretion within the ER and cell death; a pathophysiological process contributing to a range of metabolic diseases and cancers. ER stress leads to the activation of a protective signalling cascade termed the Unfolded Protein Response (UPR). However, chronic UPR activation can ultimately result in cellular apoptosis. Emerging evidence suggests that cells undergoing ER stress and UPR activation can release extracellular signals that can propagate UPR activation to target tissues in a cell non-autonomous signalling mechanism. Separately, studies have determined that the UPR plays a key regulatory role in the biosynthesis of bioactive signalling lipids including sphingolipids and ceramides. Here we weigh the evidence to combine these concepts and propose that during ER stress, UPR activation drives the biosynthesis of ceramide lipids, which are exported and function as cell non-autonomous signals to propagate UPR activation in target cells and tissues.

Keywords:  ceramide; endoplasmic reticulum; lipidomics; lipids; paracrine signalling; skeletal muscle; unfolded protein response

DOI:  https://doi.org/10.1002/bies.202300029
Pulm Pharmacol Ther. 2023 May 16. pii: S1094-5539(23)00030-5. [Epub ahead of print] 102218

Chronic obstructive pulmonary disease and emerging ER stress-related therapeutic targets.

Jia Wen Yeap, Irfhan Ali Hyder Ali, Baharudin Ibrahim, Mei Lan Tan.

  COPD pathogenesis is frequently associated with endoplasmic reticulum stress (ER stress) progression. Targeting the major unfolded protein response (UPR) branches in the ER stress pathway may provide pharmacotherapeutic selection strategies for treating COPD and enable relief from its symptoms. In this study, we aimed to systematically review the potential role of the ER stress inhibitors of major UPR branches (IRE1, PERK, and ATF6) in COPD-related studies and determine the current stage of knowledge in this field. The systematic review was carried out adhering to the PRISMA checklist based on published studies obtained from specific keyword searches of three databases, namely PubMed, ScienceDirect and Springer Database. The search was limited to the year 2000-2022 which includes all in vitro studies, in vivo studies and clinical trials related to the application of ER stress inhibitors toward COPD-induced models and disease. The risk of bias was evaluated using the QUIN, SYRCLE, revised Cochrane risk of bias tool for randomized trials (RoB 2.0) and NIH tool respectively. A total of 7828 articles were screened from three databases and a final total of 37 studies were included in the review. The ER stress and UPR pathways are potentially useful to prevent COPD progression and attenuate the exacerbation of COPD and related symptoms. Interestingly, the off-target effects from inhibition of the UPR pathway may be desirable or undesirable depending on context and therapeutic applications. Targeting the UPR pathway could have complex consequences as the production of ER molecules involved in folding may be impaired which could continuously provoke misfolding of proteins. Although several emerging compounds were noted to be potentially useful for targeted therapy against COPD, clinical studies have yet to be thoroughly explored.

Keywords:  COPD; Chronic obstructive pulmonary disease; ER stress; ER stress Inhibitor; UPR pathway

DOI:  https://doi.org/10.1016/j.pupt.2023.102218
Curr Opin Physiol. 2022 Aug;pii: 100552. [Epub ahead of print]28

IRE1/XBP1 and endoplasmic reticulum signaling - from basic to translational research for cardiovascular disease.

Fangyi Fu, Shirin Doroudgar.

Most cellular protein synthesis, including synthesis of membrane-targeted and secreted proteins, which are critical for cellular and organ crosstalk, takes place at the endoplasmic reticulum (ER), placing the ER at the nexus of cellular signaling, growth, metabolism, and stress sensing. Ample evidence has established the dysregulation of protein homeostasis and the ER unfolded protein response (UPR) in cardiovascular disease. However, the mechanisms of stress sensing and signaling in the ER are incompletely defined. Recent studies have defined notable functions for the inositol-requiring kinase 1 (IRE1)/X-box- binding protein-1 (XBP1) branch of the UPR in regulation of cardiac function. This review highlights the mechanisms underlying IRE1 activation and the IRE1 interactome, which reveals unexpected functions for the UPR and summarizes our current understanding of the functions of IRE1 in cardiovascular disease.

DOI: https://doi.org/10.1016/j.cophys.2022.100552
bioRxiv. 2023 May 02. pii: 2023.05.02.538835. [Epub ahead of print]

The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB/PDIA1 contributing to liver damage and fibrosis.

Younis Hazari, Hery Urra, Valeria A Garcia Lopez, Javier Diaz, Giovanni Tamburini, Mateus Milani, Philippe Pihan, Sylvere Durand, Fanny Aprahamia, Reese Baxter, Menghao Huang, X Charlie Dong, Helena Vihinen, Ana Batista-Gonzalez, Patricio Godoy, Alfredo Criollo, Vlad Ratziu, Fabienne Foufelle, Jan G Hengstler, Eija Jokitalo, Beatrice Bailly-Maitre, Jessica L Maiers, Lars Plate, Guido Kroemer, Claudio Hetz.

Collagen is one the most abundant proteins and the main cargo of the secretory pathway, contributing to hepatic fibrosis and cirrhosis due to excessive deposition of extracellular matrix. Here we investigated the possible contribution of the unfolded protein response, the main adaptive pathway that monitors and adjusts the protein production capacity at the endoplasmic reticulum, to collagen biogenesis and liver disease. Genetic ablation of the ER stress sensor IRE1 reduced liver damage and diminished collagen deposition in models of liver fibrosis triggered by carbon tetrachloride (CCl 4 ) administration or by high fat diet. Proteomic and transcriptomic profiling identified the prolyl 4-hydroxylase (P4HB, also known as PDIA1), which is known to be critical for collagen maturation, as a major IRE1-induced gene. Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the ER and altered secretion, a phenotype rescued by P4HB overexpression. Taken together, our results collectively establish a role of the IRE1/P4HB axis in the regulation of collagen production and its significance in the pathogenesis of various disease states.

DOI: https://doi.org/10.1101/2023.05.02.538835
Traffic. 2023 May 17.

Pseudophosphatase STYXL1 depletion enhances glucocerebrosidase trafficking to lysosomes via ER stress.

Saloni Patel, Anshul Milap Bhatt, Priyanka Bhansali, Subba Rao Gangi Setty.

  Pseudophosphatases are catalytically inactive but share sequence and structural similarities with classical phosphatases. STYXL1 is a pseudophosphatase that belongs to the family of dual-specificity phosphatases and is known to regulate stress granule formation, neurite formation and apoptosis in different cell types. However, the role of STYXL1 in regulating cellular trafficking or the lysosome function has not been elucidated. Here, we show that the knockdown of STYXL1 enhances the trafficking of β-glucocerebrosidase (β-GC) and its lysosomal activity in HeLa cells. Importantly, the STYXL1-depleted cells display enhanced distribution of endoplasmic reticulum (ER), late endosome and lysosome compartments. Further, knockdown of STYXL1 causes the nuclear translocation of unfolded protein response (UPR) and lysosomal biogenesis transcription factors. However, the upregulated β-GC activity in the lysosomes is independent of TFEB/TFE3 nuclear localization in STYXL1 knockdown cells. The treatment of STYXL1 knockdown cells with 4-PBA (ER stress attenuator) significantly reduces the β-GC activity equivalent to control cells but not additive with thapsigargin, an ER stress activator. Additionally, STYXL1-depleted cells show the enhanced contact of lysosomes with ER, possibly via increased UPR. The depletion of STYXL1 in human primary fibroblasts derived from Gaucher patients showed moderately enhanced lysosomal enzyme activity. Overall, these studies illustrated the unique role of pseudophosphatase STYXL1 in modulating the lysosome function both in normal and lysosome-storage disorder cell types. Thus, designing small molecules against STYXL1 possibly can restore the lysosome activity by enhancing ER stress in Gaucher disease.

Keywords:  ER stress and Gaucher disease; STYXL1; TFE3; TFEB; lysosome; pseudophosphatase; β-glucocerebrosidase

DOI:  https://doi.org/10.1111/tra.12886
Clin Immunol. 2023 May 10. pii: S1521-6616(23)00138-9. [Epub ahead of print] 109639

Endoplasmic reticulum stress impairs the immune regulation property of macrophages in asthmatic patients.

Lihua Mo, Yu Liu, Xuejie Xu, Xinxin Wang, Shuang Zhang, Suqin Hu, Yongjin Wu, Zhiyuan Tang, Qinmiao Huang, Jing Li, Xizhuo Sun, Pingchang Yang.

  The current study aims to characterize the counteraction of M2 cells in response to Endoplasmic reticulum (ER) stress. ER stress was detected in bronchoalveolar lavage fluids (BALF) Mϕs, which was at unresolved state in asthma patients. A positive correlation was detected between ER stress in Mϕs and lung functions/allergic mediators/Th2 cytokines in BALF or specific IgE in the serum. Levels of immune regulatory mediator in the BALF were negatively correlated to ER stress in BALF Mϕs. The ER stress state influenced the immune regulatory property of BALF Mϕ. Exposure to environmental pollutant, 3-metheyl-4-nitrophenol, exacerbated ER stress in Mϕ, which affected the Mϕ phenotyping. Exacerbation of ER stress suppressed the expression of IL-10 and programmed cell death protein-1 (PD-1) in Mϕs by increasing the expression of the ring finger protein 20 (Rnf20). Conditional inhibition of Rnf20 in Mϕs attenuated experimental airway allergy.

Keywords:  Air pollution; Allergy; Endoplasmic reticulum stress; Immune regulation; Macrophage

DOI:  https://doi.org/10.1016/j.clim.2023.109639
Cells. 2023 04 29. pii: 1283. [Epub ahead of print]12(9):

The RNA Demethylase ALKBH5 Maintains Endoplasmic Reticulum Homeostasis by Regulating UPR, Autophagy, and Mitochondrial Function.

Panneerdoss Subbarayalu, Pooja Yadav, Santosh Timilsina, Daisy Medina, Kunal Baxi, Robert Hromas, Ratna K Vadlamudi, Yidong Chen, Patrick Sung, Manjeet K Rao.

  Eukaryotic cells maintain cellular fitness by employing well-coordinated and evolutionarily conserved processes that negotiate stress induced by internal or external environments. These processes include the unfolded protein response, autophagy, endoplasmic reticulum-associated degradation (ERAD) of unfolded proteins and altered mitochondrial functions that together constitute the ER stress response. Here, we show that the RNA demethylase ALKBH5 regulates the crosstalk among these processes to maintain normal ER function. We demonstrate that ALKBH5 regulates ER homeostasis by controlling the expression of ER lipid raft associated 1 (ERLIN1), which binds to the activated inositol 1, 4, 5,-triphosphate receptor and facilitates its degradation via ERAD to maintain the calcium flux between the ER and mitochondria. Using functional studies and electron microscopy, we show that ALKBH5-ERLIN-IP3R-dependent calcium signaling modulates the activity of AMP kinase, and consequently, mitochondrial biogenesis. Thus, these findings reveal that ALKBH5 serves an important role in maintaining ER homeostasis and cellular fitness.

Keywords:  ALKBH5; ER homeostasis; ERLIN1; autophagy; m6A; mitochondria; unfolded protein response

DOI:  https://doi.org/10.3390/cells12091283
Biol Pharm Bull. 2023 May 13.

Forsythiaside A alleviates Lipopolysacchrride-induced acute liver Injury through inhibiting endoplasmic reticulum stress and NLRP3 inflammasome activation.

Jing-Nan Fu, Shu-Chang Liu, Yi Chen, Jie Zhao, Ning Lu, Tao Ma.

  The liver is the primary site of inflammation caused by bacterial endotoxins in sepsis, and septic acute liver injury (SALI) is usually associated with poor outcomes in sepsis. Forsythiaside A (FTA), an active constituent of Forsythia suspensa, has been reported to have anti-inflammatory properties, antioxidant properties, and protective properties against neuroinflammation, sepsis, and edema.Therefore, the purpose of the present study was to examine FTA's potential effects on lipopolysaccharide (LPS)-induced SALI in mice.Our results indicated that pretreatment with FTA significantly attenuated aspartate aminotransferase (AST) and aminoleucine transferase (ALT) levels in plasma, ameliorated histopathological damage, inhibited hepatocyte apoptosis, diminished the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the liver from mice exposed to LPS. Furthermore, our data showed that the administration of LPS resulted in robust endoplasmic reticulum (ER) stress response, as evidenced by GRP78 upregulation, p-PERK activation, elF2α phosphorylation, and ATF4 and CHOP overexpression in the liver. This, in turn, led to nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation, including the cleavage of caspase-1, secretion of IL-1β, and pyroptotic cell death in the liver specimens. Importantly, the ER stress response induced by the LPS challenge was blocked by FTA administration. Correspondingly, NLRP3 inflammasome activation was significantly ameliorated by the pretreatment with FTA. Thus, we demonstrated that FTA pretreatment could protect mice from LPS-induced SALI, and its protective effects were possibly mediated by inhibiting ER stress response and subsequent NLRP3 inflammasome activation.

Keywords:  Forsythiaside A; Lipopolysacchrride; endoplasmic reticulum stress; liver injury; mice; nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome

DOI:  https://doi.org/10.1248/bpb.b23-00137
J Invest Dermatol. 2023 May 17. pii: S0022-202X(23)02060-2. [Epub ahead of print]

GALECTIN-12 REGULATES IMMUNE RESPONSES IN THE SKIN THROUGH SEBACEOUS GLANDS.

Feng-Jen Lin, Yun-Hsi Huang, Ching-Han Tsao, Wei-Chen Hsieh, Yuan-Hsin Lo, Christos C Zouboulis, Hung-Lin Chen, Fu-Tong Liu.

  Sebaceous glands are holocrine glands that produce sebum, which primarily contains lipids that help maintain the barrier function of the skin. Dysregulated lipid production contributes to the progression of some diseases characterized by dry skin, including atopic dermatitis. Although the lipid production of sebaceous glands has been well studied, few studies have assessed their role in skin immune responses. We found that sebaceous glands and sebocytes expressed interleukin (IL)-4 receptor and produced high levels of Th2-associated inflammatory mediators following IL-4 treatment, suggesting immunomodulatory effects. Galectin-12 is a lipogenic factor expressed in sebocytes that affects their differentiation and proliferation. Using galectin-12-knockdown sebocytes, we demonstrated that galectin-12 regulated immune response in cells exposed to IL-4 and promoted CCL26 expression by upregulating PPARγ. Moreover, galectin-12 suppresses the expression of endoplasmic reticulum (ER) stress-response molecules and CCL26 upregulation by IL-4 was reversed following sebocyte treatment with inducers of ER stress, suggesting that galectin-12 controls IL-4 signaling by suppressing ER stress. Using galectin-12-knockout mice, we demonstrated that galectin-12 positively regulated the IL-4-induced enlargement of sebaceous glands and development of an atopic dermatitis-like phenotype. Thus, galectin-12 regulates the skin immune response through promoting PPARγ expression and suppressing ER stress in sebaceous glands.

Keywords:  Atopic dermatitis; CCL26; Galectin-12; PPARγ; Sebaceous gland

DOI:  https://doi.org/10.1016/j.jid.2023.03.1684
J Int Med Res. 2023 May;51(5): 3000605231173272

Homeodomain-interacting protein kinase 2 regulates NLRP3 inflammasome activation through endoplasmic reticulum stress in septic liver injury.

Lijun Cao, Min Wen, Zhiqiang Hu, Weihe Jia, Jiayan Lin, Bo Hu, Gang Wu, Shengchuang Tong, Qinglin Chen, Xingming Liu, Xuhao Weng.

  OBJECTIVE: Septic liver injury is a major burden for the clinical management of sepsis. Hepatocyte cell death plays a crucial pathophysiological role in sepsis. A recent study proposed that NLRP3 inflammasome-mediated pyroptosis participates in septic liver injury. Therefore, investigating the mechanism controlling this process may help manage sepsis.METHODS: We investigated the role of homeodomain-interacting protein kinase 2 (HIPK2) in regulating the NLRP3 inflammasome in vivo using mouse models and in vitro in primary hepatocytes.
RESULTS: HIPK2 could improve liver injury and survival in a mouse model of sepsis. Overexpression of HIPK2 could suppress NLRP3 and caspase-1-p20 expression, while HIPK2 knockdown led to higher levels of these two molecules. Importantly, HIPK2 could suppress endoplasmic reticulum (ER) stress. Pharmacologically inhibiting ER stress could abolish activation of the NLRP3 inflammasome in hepatocytes with HIPK2 knockdown.
CONCLUSION: HIPK2 can regulate ER stress and NLRP3 inflammasome activation in the liver during sepsis, and HIPK2-mediated suppression of ER stress participates in regulating NLRP3 inflammasome activation. The present study highlights the role of HIPK2 in regulating the inflammasome in septic liver injury, which may serve as a target for managing sepsis.

Keywords:  Homeodomain-interacting protein kinase 2; NLRP3; endoplasmic reticulum; inflammasome; liver injury; sepsis

DOI:  https://doi.org/10.1177/03000605231173272
Mol Cells. 2023 May 16.

Structure-Based Insight on the Mechanism of N-Glycosylation Inhibition by Tunicamycin.

Danbi Yoon, Ju Heun Moon, Anna Cho, Hyejoon Boo, Jeong Seok Cha, Yoonji Lee, Jiho Yoo.

  N-glycosylation, a common post-translational modification, is widely acknowledged to have a significant effect on protein stability and folding. N-glycosylation is a complex process that occurs in the endoplasmic reticulum (ER) and requires the participation of multiple enzymes. GlcNAc-1-P-transferase (GPT) is essential for initiating N-glycosylation in the ER. Tunicamycin is a natural product that inhibits N-glycosylation and produces ER stress, and thus it is utilized in research. The molecular mechanism by which GPT triggers N-glycosylation is discussed in this review based on the GPT structure. Based on the structure of the GPT-tunicamycin complex, we also discuss how tunicamycin reduces GPT activity, which prevents N-glycosylation. This review will be highly useful for understanding the role of GPT in the N-glycosylation of proteins, as well as presents a potential for considering tunicamycin as an antibiotic treatment.

Keywords:  DPAGT1; GPT; GlcNAc-1-P transferase; N-glycosylation; tunicamycin

DOI:  https://doi.org/10.14348/molcells.2023.0001
Stem Cells Transl Med. 2023 May 15. 12(5): 293-306

Patient-Specific iPSC-Derived Models Link Aberrant Endoplasmic Reticulum Stress Sensing and Response to Juvenile Osteochondritis Dissecans Etiology.

Giuliana E Salazar-Noratto, Catriana C Nations, Hazel Y Stevens, Maojia Xu, Sean Gaynard, Claire Dooley, Nica de Nijs, Katya McDonagh, Sanbing Shen, S Clifton Willimon, Frank Barry, Robert E Guldberg.

  Juvenile osteochondritis dissecans (JOCD) is a pediatric disease, which begins with an osteonecrotic lesion in the secondary ossification center which, over time, results in the separation of the necrotic fragment from the parent bone. JOCD predisposes to early-onset osteoarthritis. However, the knowledge gap in JOCD pathomechanisms severely limits current therapeutic strategies. To elucidate its etiology, we conducted a study with induced pluripotent stem cells (iPSCs) from JOCD and control patients. iPSCs from skin biopsies were differentiated to iMSCs (iPSC-derived mesenchymal stromal cells) and subjected to chondrogenic and endochondral ossification, and endoplasmic reticulum (ER)-stress induction assays. Our study, using 3 JOCD donors, showed that JOCD cells have lower chondrogenic capability and their endochondral ossification process differs from control cells; yet, JOCD- and control-cells accomplish osteogenesis of similar quality. Our findings show that endoplasmic reticulum stress sensing and response mechanisms in JOCD cells, which partially regulate chondrocyte and osteoblast differentiation, are related to these differences. We suggest that JOCD cells are more sensitive to ER stress than control cells, and in pathological microenvironments, such as microtrauma and micro-ischemia, JOCD pathogenesis pathways may be initiated. This study is the first, to the best of our knowledge, to realize the important role that resident cells and their differentiating counterparts play in JOCD and to put forth a novel etiological hypothesis that seeks to consolidate and explain previously postulated hypotheses. Furthermore, our results establish well-characterized JOCD-specific iPSC-derived in vitro models and identified potential targets which could be used to improve diagnostic tools and therapeutic strategies in JOCD.

Keywords:  articulation disorders; chondrogenesis; endoplasmic reticulum stress; induced pluripotent stem cells; osteochondritis dissecans; osteogenesis

DOI:  https://doi.org/10.1093/stcltm/szad018
Cell Mol Life Sci. 2023 May 19. 80(6): 157

Overexpression of VIRMA confers vulnerability to breast cancers via the m6A-dependent regulation of unfolded protein response.

Quintin Lee, Renhua Song, Dang Anh Vu Phan, Natalia Pinello, Jessica Tieng, Anni Su, James M Halstead, Alex C H Wong, Michelle van Geldermalsen, Bob S-L Lee, Bowen Rong, Kristina M Cook, Mark Larance, Renjing Liu, Fei Lan, Jessamy C Tiffen, Justin J-L Wong.

  Virilizer-like m6A methyltransferase-associated protein (VIRMA) maintains the stability of the m6A writer complex. Although VIRMA is critical for RNA m6A deposition, the impact of aberrant VIRMA expression in human diseases remains unclear. We show that VIRMA is amplified and overexpressed in 15-20% of breast cancers. Of the two known VIRMA isoforms, the nuclear-enriched full-length but not the cytoplasmic-localised N-terminal VIRMA promotes m6A-dependent breast tumourigenesis in vitro and in vivo. Mechanistically, we reveal that VIRMA overexpression upregulates the m6A-modified long non-coding RNA, NEAT1, which contributes to breast cancer cell growth. We also show that VIRMA overexpression enriches m6A on transcripts that regulate the unfolded protein response (UPR) pathway but does not promote their translation to activate the UPR under optimal growth conditions. Under stressful conditions that are often present in tumour microenvironments, VIRMA-overexpressing cells display enhanced UPR and increased susceptibility to death. Our study identifies oncogenic VIRMA overexpression as a vulnerability that may be exploited for cancer therapy.

Keywords:  Breast cancer; Endoplasmic reticulum stress; Messenger RNA; N6-methyladenosine (m6a); Unfolded protein response; VIRMA

DOI:  https://doi.org/10.1007/s00018-023-04799-4
Oncoscience. 2023 ;10 9-10

UPR-induced ovarian cancer cell fusion: a mechanism favoring drug resistance?

Melisa Husein, Patrick Petignat, Marie Cohen.



Keywords:  drug resistance; ovarian cancer; polyploidy giant cancer cell; unfolded protein response

DOI:  https://doi.org/10.18632/oncoscience.575