bims-unfpre Biomed News
on Unfolded protein response
Issue of 2022–09–18
twelve papers selected by
Susan Logue, University of Manitoba
  1. Folate enzyme MTHFD2 links one-carbon metabolism to unfolded protein response in glioblastoma.
  2. Epithelial ER Stress Enhances the Risk of Muc5b Associated Lung Fibrosis.
  3. ER Stress-Induced Sphingosine-1-Phosphate Lyase Phosphorylation Potentiates the Mitochondrial Unfolded Protein Response.
  4. Transcription factor EB protects against endoplasmic reticulum stress in human coronary artery endothelial cells.
  5. ER stress induces myocardial dysfunction and cardiac autophagy in Sestrin2 knockout mice.
  6. A systems biological analysis of the ATF4-GADD34-CHOP regulatory triangle upon endoplasmic reticulum stress.
  7. Endoplasmic reticulum stress promotes nuclear translocation of calmodulin, which activates phenotypic switching of vascular smooth muscle cells.
  8. Development and validation of a prognosis prediction model based on 18 endoplasmic reticulum stress-related genes for patients with lung adenocarcinoma.
  9. Inhibition of the IRE1/JNK pathway in renal tubular epithelial cells attenuates ferroptosis in acute kidney injury.
  10. XBP1 impacts lung adenocarcinoma progression by promoting plasma cell adaptation to the tumor microenvironment.
  11. CaMKII orchestrates endoplasmic reticulum stress and apoptosis in doxorubicin-induced cardiotoxicity by regulating the IRE1α/XBP1s pathway.
  12. Glycerolipid Synthesis and Lipid Droplet Formation in the Endoplasmic Reticulum.
  1. Cancer Lett. 2022 Sep 08. pii: S0304-3835(22)00387-1. [Epub ahead of print] 215903
    Folate enzyme MTHFD2 links one-carbon metabolism to unfolded protein response in glioblastoma.
    Zhiyuan Zhu, Karrie Mei-Yee Kiang, Ning Li, Jiaxin Liu, Pingde Zhang, Lei Jin, Xiaozheng He, Shizhong Zhang, Gilberto Ka-Kit Leung.
      The mitochondrial folate enzyme methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) has shown oncogenic roles in various cancers and may have non-metabolic functions. This study investigated the role of MTHFD2 in glioblastoma pathogenesis. We find that MTHFD2 expression is enriched in gliomas by analysing public databases and clinical specimens. RNA interference (RNAi) and inhibitor of MTHFD2 hamper the proliferation of glioblastoma and induce apoptosis in cell lines, glioma stem-like cells (GSCs) and patient-derived xenografts (PDX). Metabolomic analyses show that MTHFD2 depletion suppresses the central carbon metabolic pathways, including glycolysis, the pentose phosphate pathway (PPP), and the tricarboxylic acid (TCA) cycle. GSEA reveals a novel non-metabolic function of MTHFD2 in association with the unfolded protein response (UPR). MTHFD2 depletion activates the PERK/eIF2α axis which contributes to translation inhibition and apoptosis; these effects are attenuated by a PERK inhibitor. Mechanistically, MTHFD2 may be linked to UPR via the post-transcriptionally regulation of chaperone protein GRP78. In conclusion, MTHFD2 could be a promising therapeutic target for glioblastoma. Besides its canonical role, MTHFD2 may contribute to glioblastoma pathogenesis via UPR, highlighting a newly identified functional link between one-carbon metabolism and cell stress response.
    Keywords:  ER stress; Metabolic reprogramming; Metabolomics; Non-metabolic; RNA interference
    DOI:  https://doi.org/10.1016/j.canlet.2022.215903
  2. Am J Respir Cell Mol Biol. 2022 Sep 15.
    Epithelial ER Stress Enhances the Risk of Muc5b Associated Lung Fibrosis.
    Evgenia Dobrinskikh, Corinne E Hennessy, Jonathan S Kurche, Eunjoo Kim, Alani M Estrella, Jonathan Cardwell, Ivana V Yang, David A Schwartz.
      The gain-of-function minor allele of the MUC5B promoter (rs35705950) is the strongest risk factor for idiopathic pulmonary fibrosis (IPF), a devastating fibrotic lung disease that leads to progressive respiratory failure in adults. We have previously demonstrated that Muc5b overexpression in mice worsens lung fibrosis following bleomycin exposure and have hypothesized that excess Muc5b promotes endoplasmic reticulum (ER) stress and apoptosis, stimulating fibrotic lung injury. Here, we report that ER stress pathway members ATF4 and ATF6 co-express with MUC5B in epithelia of the distal IPF airway and honeycomb cyst, and this is more pronounced in carriers of the gain-of-function MUC5B promoter variant. Similarly, in mice exposed to bleomycin, Muc5b expression is temporally associated with markers of ER stress. Using bulk and single cell RNA sequencing (scRNA-seq) in bleomycin-exposed mice, we found that pathologic ER-stress associated transcripts Atf4 and Ddit3 were elevated in alveolar epithelia of SFTPC-Muc5b transgenic (SFTPC-Muc5bTg) mice relative to wild type mice. Activation of the ER stress response inhibits protein translation for most genes by phosphorylation of Eif2α, which prevents guanine exchange by Eif2B, and facilitates translation of Atf4. The integrated stress response inhibitor (ISRIB), facilitates interaction of phosphorylated Eif2α with Eif2B, overcoming translation inhibition associated with ER stress and reducing Atf4 translation. We found that a single dose of ISRIB diminished Atf4 translation in SFTPC-Muc5bTg mice following bleomycin injury. Moreover, ISRIB resolved the exaggerated fibrotic response of SFTPC-Muc5bTg mice to bleomycin. In summary, we demonstrate that MUC5B/Muc5b expression is associated with pathologic ER stress and that restoration of normal translation with a single dose of ISRIB promotes lung repair in bleomycin-injured Muc5b-overexpressing mice.
    Keywords:  ATF4; ER stress; Fibrosis; IPF; MUC5B
    DOI:  https://doi.org/10.1165/rcmb.2022-0252OC
  3. J Lipid Res. 2022 Sep 10. pii: S0022-2275(22)00112-2. [Epub ahead of print] 100279
    ER Stress-Induced Sphingosine-1-Phosphate Lyase Phosphorylation Potentiates the Mitochondrial Unfolded Protein Response.
    Asli D Yildirim, Mevlut Citir, Asli E Dogan, Zehra Veli, Zehra Yildirim, Ozlem Tufanli, Alexis Traynor Kaplan, Carsten Schultz, Ebru Erbay.
      The unfolded protein response (UPR) is an elaborate signaling network that evolved to maintain proteostasis in the endoplasmic reticulum (ER) and mitochondria (mt). These organelles are functionally and physically associated and consequently, their stress responses are often intertwined. It is unclear how these two adaptive stress responses are coordinated during ER stress. The inositol-requiring enzyme-1 (IRE1), a central ER stress sensor and proximal regulator of the UPRER, harbors dual kinase and endoribonuclease (RNase) activities. IRE1 RNase activity initiates the transcriptional layer of the UPRER, but IRE1's kinase substrate(s) and their functions are largely unknown. Here, we discovered that sphingosine 1-phosphate (S1P) lyase (SPL), the enzyme that degrades S1P, is a substrate for the mammalian IRE1 kinase. Our data show that IRE1-dependent SPL phosphorylation inhibits SPL's enzymatic activity, resulting in increased intracellular S1P levels. S1P has previously been shown to induce the activation of mitochondrial UPR (UPRmt) in nematodes. We determined that IRE1 kinase-dependent S1P induction during ER stress potentiates UPRmt signaling in mammalian cells. Phosphorylation of eukaryotic translation initiation factor 2α (eif2α) is recognized as a critical molecular event for UPRmt activation in mammalian cells. Our data further demonstrate that inhibition of the IRE1-SPL axis abrogates the activation of two eif2α kinases, namely double-stranded RNA-activated protein kinase (PKR) and PKR-like ER kinase (PERK) upon ER stress. These findings show that the IRE1-SPL axis plays a central role in coordinating the adaptive responses of both organelles to ER stress in mammalian cells.
    Keywords:  Adaptive Stress Response; Endoplasmic Reticulum; Endoribonuclease; Eukaryotic Translation Initiation Factor 2α; IRE1-SPL axis; Inositol-Requiring Enzyme-1; Kinase; Mitochondria; Proteostasis; Signaling Networks
    DOI:  https://doi.org/10.1016/j.jlr.2022.100279
  4. Eur J Pharmacol. 2022 Sep 12. pii: S0014-2999(22)00535-0. [Epub ahead of print] 175274
    Transcription factor EB protects against endoplasmic reticulum stress in human coronary artery endothelial cells.
    Michael J Haas, Victoria Feng, Krista Gonzales, Priyanka Bikkina, Marie Angelica Landicho, Arshag D Mooradian.
      Oxidative stress and endoplasmic reticulum (ER) stress promote atherogenesis while transcription factor EB (TFEB) inhibits atherosclerosis. Since reducing oxidative stress with antioxidants have failed to reduce atherosclerosis possibly because of aggravation of ER stress, we studied the effect of TFEB on ER stress in human coronary artery endothelial cells. ER stress was measured using the secreted alkaline phosphatase assay. Expression and phosphorylation of key mediators of unfolded protein response (UPR). TFEB, inositol-requiring enzyme 1α (IRE1α), phospho-IRE1α, protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), phospho-PERK, and activating transcription factor 6 (ATF6) expression were measured by Western blot. The effect of TFEB gain- and loss-of-function on ER stress were assessed with a plasmid expressing a constitutively active form of TFEB and via siRNA-mediated silencing, respectively. Treatment with tunicamycin (TM) and thapsigargin (TG) increased TFEB expression by 42.8% and 42.3%, respectively. In HCAEC transfected with the TFEB siRNA, treatment with either TM, TG or high-dextrose increased IRE1α and PERK phosphorylation and ATF6 levels significantly more compared to cells transfected with the control siRNA and treated similarly. Furthermore, transient transfection with a plasmid expressing a constitutively active form of TFEB reduced ER stress. Increased expression of TFEB inhibited ER stress in HCAEC treated with pharmacologic (TM and TG) and physiologic (high-dextrose) ER stress inducers, while TFEB knockout aggravated ER stress caused by these ER stress inducers. TFEB-mediated ER stress reduction may contribute to its anti-atherogenic effects in HCAEC and may be a novel target for drug development.
    Keywords:  Atherosclerosis; Cardiovascular disease; ER Stress; HCAEC; Transcription factor EB
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175274
  5. Am J Transl Res. 2022 ;14(8): 5800-5811
    ER stress induces myocardial dysfunction and cardiac autophagy in Sestrin2 knockout mice.
    Jie Zhang, Linlin Yao, Shaohua Li, Misbahul Ferdous, Peng Zhao.
       OBJECTIVES: Sestrin2 is an essential regulator of the cellular adaptive response against various stresses. The endoplasmic reticulum (ER) is critical in maintaining normal cardiac function by controlling intracellular Ca2+ accumulation, as well as protein folding and processing. Autophagy contributes to stress-associated heart dysfunction. AMP-activated protein kinase (AMPK) is important in energy homeostasis in cardiomyocytes. However, the function of Sestrin2 (Sesn2) in ER stress-induced autophagy that induces myocardial dysfunction has not been clarified. In this study, mice and cardiac tissues were treated with tunicamycin (TN), an inducer of ER stress. We then explored the roles of Sesn2 and the AMPK pathway associated with autophagy in ER stress-induced myocardial dysfunction in mice.
    METHODS: Echocardiography, contractile function analysis, intracellular Ca2+ status, and immunoblot analysis of AMPK pathway were performed, ER stress and autophagy markers were examined.
    RESULTS: The study revealed that ER stress caused significant heart dysfunction and cardiotoxicity in the mouse heart and cardiomyocytes. Biochemical analysis indicated enhanced cardiac autophagy mediated by ER stress and AMPK/mTOR activation. Sesn2 knockout exacerbated ER stress-related myocardial dysfunction due to the failed response of cardiac autophagy and AMPK/mTOR pathway activation. Further, pharmacological inhibition of AMPK or autophagy worsened TN-induced cardiac dysfunction.
    CONCLUSION: Taken together, loss of the Sesn2 protein exacerbates ER stress-induced cardiac dysfunction through the AMPK/mTOR signaling cascade and loss of autophagy response.
    Keywords:  ER stress; Sestrin2; autophagy; cardiac dysfunction
  6. FEBS Open Bio. 2022 Sep 13.
    A systems biological analysis of the ATF4-GADD34-CHOP regulatory triangle upon endoplasmic reticulum stress.
    Margita Márton, Gábor Bánhegyi, Norbert Gyöngyösi, Eszter Éva Kálmán, Aladár Pettkó-Szandtner, Krisztina Káldi, Orsolya Kapuy.
      Endoplasmic reticulum stress-dependent accumulation of incorrectly folded proteins leads to activation of the unfolded protein response. The role of the UPR is to avoid cell damage and restore the homeostatic state by autophagy; however, excessive ER stress results in apoptosis. Here, we investigated the ER stress-dependent feedback loops inside one of the UPR branches by focusing on PERK-induced ATF4 and its two targets, called CHOP and GADD34. Our goal was to qualitatively describe the dynamic behaviour of the system by exploring the key regulatory motifs using both molecular and theoretical biological techniques. Using the HEK293T cell line as a model system, we confirmed that the life-or-death decision is strictly regulated. We investigated the dynamic characteristics of the crucial elements of the PERK pathway at both the RNA and protein level upon tolerable and excessive levels of ER stress. Of particular note, inhibition of GADD34 or CHOP resulted in various phenotypes upon high levels of ER stress. Our computer simulations suggest the existence of two new feedback loops inside the UPR. First, GADD34 seems to have a positive effect on ATF4 activity, while CHOP inhibits it. We claim that these newly described feedback loops ensure the fine-tuning of the ATF4-dependent stress response mechanism of the cell.
    Keywords:  ATF4-GADD34-CHOP; PERK pathway; endoplasmic reticulum stress; feedback loop; systems biology; unfolded protein response
    DOI:  https://doi.org/10.1002/2211-5463.13484
  7. Biochem Biophys Res Commun. 2022 Aug 28. pii: S0006-291X(22)01208-6. [Epub ahead of print]628 155-162
    Endoplasmic reticulum stress promotes nuclear translocation of calmodulin, which activates phenotypic switching of vascular smooth muscle cells.
    Tomoyuki Uchida, Tetsuro Oda, Takeshi Yamamoto, Masako Inamitsu, Chihiro Sakai, Hitoshi Uchinoumi, Takeshi Suetomi, Yoshihide Nakamura, Yoko Okamoto, Satomi Tateda, Shohei Fujii, Shinji Tanaka, Junya Nawata, Takayuki Okamura, Shigeki Kobayashi, Masafumi Yano.
       BACKGROUND AND AIMS: Increased endoplasmic reticulum (ER) stress is strongly associated with the phenotypic switching of vascular smooth muscle cells (VSMCs) in atherosclerosis. Depletion of the ER Ca2+ content is one of the leading causes of increased ER stress in VSMCs. The ryanodine receptor (RyR) is a major Ca2+ release channel in the sarcoplasmic reticulum membrane. Calmodulin (CaM), which binds to RyR (CaM-RyR), stabilizes the closed state of RyR in the resting state in normal cells. Defective CaM-RyR interactions can cause abnormal Ca2+ leakage through RyR, resulting in decreased Ca2+ content, indicating that defective CaM-RyR interactions may be a cause of increased ER stress. Herein, we used a mouse VSMCs to assess whether CaM-RyR plays a pivotal role in VSMCs phenotypic switching, which is caused by ER stress, and whether dantrolene, which enhances the binding affinity of CaM to RyR, affects VSMCs phenotypic switching.
    METHODS AND RESULTS: Tunicamycin was used to mimic ER stress in vitro. Tunicamycin-induced ER stress caused CaM to dissociate from the RyR and translocate to the nucleus, which stimulated phenotypic switching through the activation of MEF2 and KLF5. Dantrolene suppressed tunicamycin-induced apoptosis, ER stress (restoring ER Ca2+ content), and phenotypic switching of VSMCs. Suramin, which directly unbinds CaM from RyR, promoted nuclear CaM accumulation with parallel VSMCs phenotypic switching, and dantrolene prevented these effects.
    CONCLUSIONS: We observed that ER stress causes CaM translocation to the nucleus and drives the phenotypic switching of VSMCs. Thus, restoration of the binding affinity of CaM to RyR may be a therapeutic target for atherosclerosis.
    Keywords:  Calmodulin; Dantrolene; Endoplasmic reticulum stress; Phenotypic switching; Ryanodine receptor
    DOI:  https://doi.org/10.1016/j.bbrc.2022.08.069
  8. Front Oncol. 2022 ;12 902353
    Development and validation of a prognosis prediction model based on 18 endoplasmic reticulum stress-related genes for patients with lung adenocarcinoma.
    Long Shu, Shuang Liu, Yongguang Tao.
       Background: Endoplasmic reticulum (ER) stress had a crucial impact on cell survival, proliferation, and metastasis in various cancers. However, the role of ER stress in lung adenocarcinoma remains unclear.
    Method: Gene expression and clinical data of lung adenocarcinoma (LUAD) samples were extracted from The Cancer Genome Atlas (TCGA) and three Gene Expression Omnibus (GEO) datasets. ER stress score (ERSS) was constructed based on hub genes selected from 799 ER stress-related genes by least absolute shrinkage and selection operator (LASSO) regression. A Cox regression model, integrating ERSS and the TNM stage, was developed to predict overall survival (OS) in TCGA cohort and was validated in GEO cohorts. Gene set enrichment analysis (GSEA), single-sample GSEA (ssGSEA), and gene mutation analyses were performed to further understand the molecular features of ERSS. The tumor immune infiltration was evaluated by ESTIMATE, CIBERSORT, and xCell algorithms. The receiver operating characteristic (ROC) curves were used to evaluate the predictive value of the risk model. p< 0.05 was considered statistically significant.
    Results: One hundred fifty-seven differentially expressed genes (DEGs) were identified between tumor and para-carcinoma tissues, and 45 of them significantly correlated with OS. Next, we identified 18 hub genes and constructed ERSS by LASSO regression. Multivariate analysis demonstrated that higher ERSS (p< 0.0001, hazard ratio (HR) = 3.8, 95%CI: 2.8-5.2) and TNM stage (p< 0.0001, HR = 1.55, 95%CI: 1.34-1.8) were independent predictors for worse OS. The prediction model integrating ERSS and TNM stage performed well in TCGA cohort (area under the curve (AUC) at five years = 0.748) and three GEO cohorts (AUC at 5 years = 0.658, 0.717, and 0.739). Pathway enrichment analysis showed that ERSS significantly correlated with unfolded protein response. Meanwhile, pathways associated with the cell cycle, growth, and metabolism were significantly enriched in the high ERSS group. Patients with SMARCA4, TP53, and EGFR mutations showed significantly higher ERSS (p = 4e-04, 0.0027, and 0.035, respectively). Tissues with high ERSS exhibited significantly higher infiltration of M1 macrophages, activated dendritic cells, and lower infiltration of CD8+ T cells and B cells, which indicate an activated tumor antigen-presenting but suppressive immune response status.
    Conclusion: We developed and validated an ER stress-related risk model that exhibited great predictive value for OS in patients with LUAD. Our work also expanded the understanding of the role of ER stress in LUAD.
    Keywords:  GEO; TCGA; endoplasmic reticulum stress; lung adenocarcinoma; prediction model
    DOI:  https://doi.org/10.3389/fonc.2022.902353
  9. Front Pharmacol. 2022 ;13 927641
    Inhibition of the IRE1/JNK pathway in renal tubular epithelial cells attenuates ferroptosis in acute kidney injury.
    Yan Liang, Zhenjie Liu, Lingyun Qu, Yingzi Wang, Yali Zhou, Lulu Liang, Yanhong Guo, Lin Tang.
      Backgroud: Ferroptosis is a form of regulated cell death in ischemia-reperfusion (I/R) injury models. Acute kidney injury (AKI) induced by I/R injury can result in cell death, and subcellular structural changes, including expansion of the endoplasmic reticulum (ER), mitochondrial shrinkage, and other morphological changes. Inositol requiring enzyme 1 (IRE1) a proximal ER stress sensor, activates c-Jun NH2-terminal kinases (JNK) in response to ER stress, which is inextricably linked to ER. Method: To determine the resulting damage and relationship between ferroptosis and the IRE1/JNK pathway in AKI, we modeled AKI in I/R renal injury mice and hypoxia/reoxygenation (H/R) HK-2 cells, as in vivo and in vitro experiments, respectively. Results: In I/R renal injury mice, we found that abnormal renal function; damage of renal tubular epithelial cells; activation of the IRE1/JNK pathway and ferroptosis. Our in vitro study showed a large number of reactive oxygen species and more ferroptotic mitochondria in H/R HK-2 cells. By inhibiting IRE1/JNK in I/R renal injury mice, we observed decreased blood urea nitrogen, creatinine, and tissue injury, compared with the I/R group, we also found the markers of ferroptosis changed, including decreased 4-hydroxynonenal and increased glutathione peroxidase 4, as well as in H/R induced IRE1/JNK knock-down HK-2 cell lines (stable depletion). Furthermore, inhibition of ferroptosis could also attenuate the IRE1/JNK pathway in mice following I/R and HK-2 cells following H/R. Conclusion: We observed cross-talk between the IRE1/JNK pathway and ferroptosis in I/R or H/R induced AKI. Our findings suggest that ferroptosis plays an important role in I/R induced AKI, and that inhibition of the IRE1/JNK pathway can protect against I/R induced renal injury by inhibiting ferroptosis. The inhibition of the IRE1/JNK pathway could therefore be a feasible therapeutic target for treatment of AKI.
    Keywords:  AKI (acute kidney injury); ER stress; IRE1 (inositol-requiring enzyme 1); JNK (c-Jun N-terminal kinase); ferroptosis; tubular epithelial cells
    DOI:  https://doi.org/10.3389/fphar.2022.927641
  10. Front Genet. 2022 ;13 969536
    XBP1 impacts lung adenocarcinoma progression by promoting plasma cell adaptation to the tumor microenvironment.
    Zhaoqian Zhong, Junhao Wang, Qizheng Han, Hong Lin, Haihua Luo, Danyan Guo, Yong Jiang, Aihua Liu.
      Background: The activation of X-box binding protein 1 (XBP1) plays an essential role in the unfolded protein response (UPR) of the endoplasmic reticulum (ER). XBP1 is commonly expressed in various tumors and is closely related to tumorigenesis and progression. However, the role of XBP1 in lung adenocarcinoma (LUAD), especially the prognostic value of its alternative splicing isoforms, remains largely unknown. Methods: The LUAD datasets were retrieved from the The Cancer Genome Atlas, ArrayExpress and Gene Expression Omnibus. GEPIA2 and meta-analysis were employed to explore the prognostic value, and bioinformatics analysis with the TIMER2.0 database was used to investigate immune cell infiltration. We performed single-cell analyses to identify cell types with high XBP1 expression. In addition, polymerase chain reaction (PCR) and DNA sequencing were performed to verify the authenticity of the new spliceosome. Results: In this study, we found that high expression of XBP1 was significantly associated with a good prognosis, and XBP1 expression was significantly positively correlated with B cell infiltration in LUAD. In addition, we found that high-level expression of a novel splicing isoform, XBP1 (XBP1-003), improved the prognosis of LUAD. Protein structural analysis demonstrated that XBP1-003 has several specific protein domains that are different from those of other XBP1 isoforms, indicating a unique function of this isoform in LUAD. Conclusion: All these results suggest that XBP1 plays an antitumorigenic role in LUAD through alternative splicing, which may be related to the adaptation of plasma cells. This sheds new light on the potential strategy for LUAD prognosis evaluation and immunotherapy.
    Keywords:  alternative splicing; endoplasmic reticulum stress; lung adenocarcinoma; plasma cells; tumor microenvironment; x-box binding protein 1
    DOI:  https://doi.org/10.3389/fgene.2022.969536
  11. J Cell Mol Med. 2022 Sep 16.
    CaMKII orchestrates endoplasmic reticulum stress and apoptosis in doxorubicin-induced cardiotoxicity by regulating the IRE1α/XBP1s pathway.
    Lingheng Kong, Yimeng Zhang, Jiayi Ning, Chennian Xu, Zhenyi Wang, Jian Yang, Lifang Yang.
      Doxorubicin (Dox), an anthracycline antibiotic with potent antitumor effects, has limited clinical applications due to cumulative cardiotoxicity. Ca2+ /calmodulin-dependent protein kinase II (CaMKII) is implicated in the pathological progression of Dox-induced cardiotoxicity. This study examined the hypothesis that CaMKII exacerbates Dox-induced cardiotoxicity by promoting endoplasmic reticulum stress and apoptosis through regulation of the inositol-requiring enzyme 1α (IRE1α)/spliced X-box binding protein 1 (XBP1s) pathway. Our results demonstrated that CaMKII activation and IRE1α/XBP1s pathway were involved in Dox-treated hearts. CaMKII inhibition with KN-93 ameliorated Dox-induced cardiac dysfunction and pathological myocardial changes. In addition, CaMKII inhibition prevented Dox-induced endoplasmic reticulum stress and apoptosis. Moreover, CaMKII inhibition increased the expression of IRE1α and XBP1s in Dox-treated hearts. The IRE1α inhibitor 4μ8C blocked the protective effect of CaMKII inhibition against Dox-induced cardiotoxicity. Mechanistically, 4μ8C prevented the effects of CaMKII inhibition on Dox-induced endoplasmic reticulum stress and apoptosis by inhibiting the expression of IRE1α and XBP1s. Additionally, treatment with rhADAMTS13 decreased the protein level of thrombospondin 1 (TSP1) and the phosphorylation of CaMKII in Dox-treated human AC16 cardiomyocytes. Taken together, these results demonstrate that the ADAMTS13-TSP1 axis regulates CaMKII activation and exacerbates Dox-induced cardiotoxicity by triggering endoplasmic reticulum stress and apoptosis by inhibiting the IRE1α/XBP1s pathway.
    Keywords:  ADAMTS13-TSP1 axis; CaMKII; IRE1α/XBP1s pathway; apoptosis; cardiotoxicity; doxorubicin; endoplasmic reticulum stress
    DOI:  https://doi.org/10.1111/jcmm.17560
  12. Cold Spring Harb Perspect Biol. 2022 Sep 12. pii: a041246. [Epub ahead of print]
    Glycerolipid Synthesis and Lipid Droplet Formation in the Endoplasmic Reticulum.
    Robert V Farese, Tobias C Walther.
      More than 60 years ago, Eugene Kennedy and coworkers elucidated the endoplasmic reticulum (ER)-based pathways of glycerolipid synthesis, including the synthesis of phospholipids and triacylglycerols (TGs). The reactions of the Kennedy pathway were identified by studying the conversion of lipid intermediates and the isolation of biochemical enzymatic activities, but the molecular basis for most of these reactions was unknown. With recent progress in the cell biology, biochemistry, and structural biology in this area, we have a much more mechanistic understanding of this pathway and its reactions. In this review, we provide an overview of molecular aspects of glycerolipid synthesis, focusing on recent insights into the synthesis of TGs. Further, we go beyond the Kennedy pathway to describe the mechanisms for storage of TG in cytosolic lipid droplets and discuss how overwhelming these pathways leads to ER stress and cellular toxicity, as seen in diseases linked to lipid overload and obesity.
    DOI:  https://doi.org/10.1101/cshperspect.a041246
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