bims-unfpre 2022-07-03 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2022–07–03
eight papers selected by
Susan Logue, University of Manitoba

ATF6 prevents DNA damage and cell death in colon cancer cells undergoing ER stress.
Maternal obesity: new placental paradigms unfolded.
Endoplasmic reticulum stress modulates the fate of lung resident mesenchymal stem cell to myofibroblast via C/EBP homologous protein during pulmonary fibrosis.
Substitution of the SERCA2 Cys674 reactive thiol accelerates atherosclerosis by inducing endoplasmic reticulum stress and inflammation.
mTOR pathway mediates endoplasmic reticulum stress-induced CD4+ T cell apoptosis in septic mice.
Unfolded Protein Response-Related Signature Associates With the Immune Microenvironment and Prognostic Prediction in Osteosarcoma.
The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition.
Endoplasmic Reticulum-Targeting Near-Infrared Fluorescent Probe for CYP2J2 Activity and Its Imaging Application in Endoplasmic Reticulum Stress and Tumor.

Cell Death Discov. 2022 Jun 25. 8(1): 295

ATF6 prevents DNA damage and cell death in colon cancer cells undergoing ER stress.

Rossella Benedetti, Maria Anele Romeo, Andrea Arena, Maria Saveria Gilardini Montani, Livia Di Renzo, Gabriella D'Orazi, Mara Cirone.

Colon cancer represents one of the most common and aggressive cancers in its advanced state. Among the most innovative anti-cancer approaches, the manipulation of UPR is a promising one, effective also against cancers carrying dysfunctional p53. Interestingly, it is emerging that UPR cross-talks with DDR and that targeting the interplay between these two adaptive responses may be exploited to overcome the resistance to the single DDR- and UPR-targeting treatments. Previous studies have highlighted the role of IRE1 alpha and PERK UPR sensors on DDR, while the impact of ATF6 on this process remains under-investigated. This study shows for the first time that ATF6 sustains the expression level of BRCA-1 and protects colon cancer cells from the cytotoxic effect of ER stressors DPE and Thapsigargin. At molecular level, ATF6 activates mTOR to sustain the expression of HSP90, of which BRCA-1 is a client protein. Therefore, pharmacological or genetic inhibition of ATF6 promoted BRCA-1 degradation and increased DNA damage and cell death, particularly in combination with Adriamycin. All together this study suggests that targeting ATF6 may not only potentiate the cytotoxic effect of drugs triggering ER stress but may render colon cancer cells more sensitive to Adriamycin and possibly to other DNA damaging agents used to treat colon cancer.

DOI: https://doi.org/10.1038/s41420-022-01085-3
Trends Mol Med. 2022 Jun 24. pii: S1471-4914(22)00155-1. [Epub ahead of print]

Maternal obesity: new placental paradigms unfolded.

Carolin Brombach, Wen Tong, Dino A Giussani.

  The prevalence of maternal obesity is increasing at an alarming rate, and is providing a major challenge for obstetric practice. Adverse effects on maternal and fetal health are mediated by complex interactions between metabolic, inflammatory, and oxidative stress signaling in the placenta. Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are common downstream pathways of cell stress, and there is evidence that this conserved homeostatic response may be a key mediator in the pathogenesis of placental dysfunction. We summarize the current literature on the placental cellular and molecular changes that occur in obese women. A special focus is cast onto placental ER stress in obese pregnancy, which may provide a novel link for future investigation.

Keywords:  ER stress; gestational obesity; inflammation; oxidative stress; placental function; unfolded protein response

DOI:  https://doi.org/10.1016/j.molmed.2022.05.013
Stem Cell Res Ther. 2022 Jun 28. 13(1): 279

Endoplasmic reticulum stress modulates the fate of lung resident mesenchymal stem cell to myofibroblast via C/EBP homologous protein during pulmonary fibrosis.

Xiaoyu Yang, Wei Sun, Xiaoyan Jing, Qian Zhang, Hui Huang, Zuojun Xu.

   BACKGROUND: As a fatal interstitial lung disease, idiopathic pulmonary fibrosis (IPF) was characterized by the insidious proliferation of extracellular matrix (ECM)-producing mesenchymal cells. Recent studies have demonstrated that lung resident mesenchymal/stromal cells (LR-MSC) are the source of myofibroblasts. Endoplasmic reticulum (ER) stress is prominent in IPF lung. This study sought to investigate the effects of ER stress on the behavior of LR-MSC during pulmonary fibrosis.
METHODS: ER stress and myofibroblast differentiation of LR-MSC in patients with IPF were evaluated. Primary mouse LR-MSC was harvested and used in vitro for testing the effects of ER stress and C/EBP homologous protein (CHOP) on LR-MSC. Adoptive transplantation of LR-MSC to bleomycin-induced pulmonary fibrosis was done to test the in vivo behavior of LR-MSC and its influence on pulmonary fibrosis.
RESULTS: We found that myofibroblast differentiation of LR-MSC is associated with ER stress in IPF and bleomycin-induced mouse fibrotic lung. Tunicamycin-induced ER stress impairs the paracrine, migration, and reparative function of mouse LR-MSC to injured type 2 alveolar epithelial cells MLE-12. Overexpression of the ER stress responder C/EBP homologous protein (CHOP) facilitates the TGFβ1-induced myofibroblast transformation of LR-MSC via boosting the TGFβ/SMAD signaling pathway. CHOP knockdown facilitates engraftment and inhibits the myofibroblast transformation of LR-MSC during bleomycin-induced pulmonary fibrosis, thus promoting the efficacy of adopted LR-MSC in alleviating pulmonary fibrosis.
CONCLUSION: Our work revealed a novel role that ER stress involved in pulmonary fibrosis by influencing the fate of LR-MSC and transformed to "crime factor" myofibroblast, during which CHOP acts as the key modulator. These results indicate that pharmacies targeting CHOP or therapies based on CHOP knockdown LR-MSC may be promising ways to treat pulmonary fibrosis.

Keywords:  C/EBP homologous protein; Endoplasmic reticulum stress; Lung resident mesenchymal stem cell; Pulmonary fibrosis

DOI:  https://doi.org/10.1186/s13287-022-02966-1
Br J Pharmacol. 2022 Jun 28.

Substitution of the SERCA2 Cys674 reactive thiol accelerates atherosclerosis by inducing endoplasmic reticulum stress and inflammation.

Hang Su, Yu Mei, Shuangxue Luo, Haixia Wu, Yan He, Yasumasa Shiraishi, Pingping Hu, Richard A Cohen, Xiaoyong Tong.

   BACKGROUND AND PURPOSE: The cysteine674 (C674) thiol of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 is easily and irreversibly oxidized under atherosclerotic conditions. However, the contribution of the C674 thiol redox status in the development of atherosclerosis remains unclear. Our goal was to elucidate the possible mechanism involved.
EXPERIMENTAL APPROACH: Heterozygous SERCA2 C674S knock-in mice in which half of the C674 was substituted by serine674 (S674) were used to mimic the removal of the reactive C674 thiol which occurs under pathological conditions. Bone marrow-derived macrophages (BMDMs) and cardiac endothelial cells (ECs) were used for intracellular Ca2+ , macrophage adhesion, and protein expression analysis. The whole aorta and aortic root were isolated for histological analysis.
KEY RESULTS: Cell culture studies suggest the partial substitution of SERCA2 C674 increased intracellular Ca2+ levels and induced ER stress in both BMDMs and ECs. The release of pro-inflammatory factors and macrophage adhesion increased in SKI BMDMs. In ECs, the overexpression of S674 induced endothelial inflammation and promoted macrophage recruitment. SKI mice developed more severe atherosclerotic plaque and macrophage accumulation. Additionally, 4-phenyl butyric acid (PBA), an ER stress inhibitor, suppressed ER stress and inflammatory responses in BMDMs and ECs, and alleviate atherosclerosis in SKI mice.
CONCLUSIONS AND IMPLICATIONS: The substitution of SERCA2 C674 thiol accelerates the development of atherosclerosis by inducing ER stress and inflammation. Our findings highlight the importance of SERCA2 C674 redox state in the context of atherosclerosis and open up a novel therapeutic strategy to combat atherosclerosis.

Keywords:  SERCA2; atherosclerosis; endoplasmic reticulum stress; inflammation; macrophages

DOI:  https://doi.org/10.1111/bph.15912
Apoptosis. 2022 Jun 27.

mTOR pathway mediates endoplasmic reticulum stress-induced CD4+ T cell apoptosis in septic mice.

Guangxu Bai, Hao Wang, Na Cui.

  Endoplasmic reticulum stress (ERS) has been well documented to participate in the pathophysiological processes of apoptosis in many diseases. Inhibition of ERS ameliorates pathological organ injury. However, the upstream signaling pathways and molecular regulatory mechanisms of which are still unknown. mTOR, an evolutionarily conserved protein kinase, is a key regulator of apoptosis. Hence, in this study, a classical cecal ligation and puncture (CLP) sepsis model was constructed by using the T cell-specific knockout mTOR and TSC1 (Tuberous Sclerosis Complex, the inhibitor of mTOR signaling pathway) mice to explore the underlying signaling pathway and molecular mechanism of host immune imbalance caused by apoptosis in sepsis. We found that mTOR may modulate septic T cell apoptosis by regulating Akt-IRE1-JNK pathway. To further clarify the possible mechanism, the specific inhibitors of PI3K-Akt and IRE1-JNK were used to intervene in mice before/after CLP, respectively. By analyzing the proteins of mTOR-ERS signaling pathway and the expression of apoptosis-related proteins and genes, we found that mTOR mediated the ER stress induced CD4+ T cell apoptosis in Septic mice by negatively regulating the Akt-IRE1-JNK-Caspase 3 signaling cascades. These results indicate that mTOR-Akt-IRE1α-JNK signaling pathway mediated the Endoplasmic reticulum stress induced CD4+ T cell apoptosis in Septic mice.

Keywords:  Apoptosis; CLP; Endoplasmic reticulum stress; IRE1–JNK; Mammalian target of rapamycin

DOI:  https://doi.org/10.1007/s10495-022-01740-1
Front Genet. 2022 ;13 911346

Unfolded Protein Response-Related Signature Associates With the Immune Microenvironment and Prognostic Prediction in Osteosarcoma.

Zhao Zhang, Xincheng Liu, Debin Cheng, Jingyi Dang, Zhenzhou Mi, Yubo Shi, Lei Wang, Hongbin Fan.

  Background: Osteosarcoma is a highly malignant bone tumor commonly occurring in adolescents with a poor 5-year survival rate. The unfolded protein response (UPR) can alleviate the accumulation of misfolded proteins to maintain homeostasis under endoplasmic reticulum stress. The UPR is linked to the occurrence, progression, and drug resistance of tumors. However, the function of UPR-related genes (UPRRGs) in disease progression and prognosis of osteosarcoma remains unclear. Methods: The mRNA expression profiling and corresponding clinical features of osteosarcoma were acquired from TARGET and GEO databases. Consensus clustering was conducted to confirm different UPRRG subtypes. Subsequently, we evaluated the prognosis and immune status of the different subtypes. Functional analysis of GO, GSEA, and GSVA was used to reveal the molecular mechanism between the subtypes. Finally, four genes (STC2, PREB, TSPYL2, and ATP6V0D1) were screened to construct and validate a risk signature to predict the prognosis of patients with osteosarcoma. Result: We identified two subtypes according to the UPRRG expression patterns. The subgroup with higher immune scores, lower tumor purity, and active immune status was linked to a better prognosis. Meanwhile, functional enrichment revealed that immune-related signaling pathways varied markedly in the two subtypes, suggesting that the UPR might influence the prognosis of osteosarcoma via influencing the immune microenvironment. Moreover, prognostic signature and nomogram models were developed based on UPRRGs, and the results showed that our model has an excellent performance in predicting the prognosis of osteosarcoma. qPCR analysis was also conducted to verify the expression levels of the four genes. Conclusion: We revealed the crucial contribution of UPRRGs in the immune microenvironment and prognostic prediction of osteosarcoma patients and provided new insights for targeted therapy and prognostic assessment of the disease.

Keywords:  immune infiltration; nomogram; osteosarcoma; prognostic prediction; unfolded protein response

DOI:  https://doi.org/10.3389/fgene.2022.911346
J Biomed Sci. 2022 Jun 28. 29(1): 46

The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition.

Jia-Huang Chen, Chia-Hsien Wu, Jia-Rong Jheng, Chia-Ter Chao, Jenq-Wen Huang, Kuan-Yu Hung, Shing-Hwa Liu, Chih-Kang Chiang.

   BACKGROUND: The activation of the unfolded protein response (UPR) is closely linked to the pathogenesis of renal injuries. However, the role of XBP1, a crucial regulator of adaptive UPR, remains unclear during the transition from acute kidney injury (AKI) to chronic kidney disease (CKD).
METHODS: We characterized XBP1 expressions in different mouse models of kidney injuries, including unilateral ischemia-reperfusion injury (UIRI), unilateral ureteral obstruction, and adenine-induced CKD, followed by generating proximal tubular XBP1 conditional knockout (XBP1cKO) mice for examining the influences of XBP1. Human proximal tubular epithelial cells (HK-2) were silenced of XBP1 to conduct proteomic analysis and investigate the underlying mechanism.
RESULTS: We showed a tripartite activation of UPR in injured kidneys. XBP1 expressions were attenuated after AKI and inversely correlated with the severity of post-AKI renal fibrosis. XBP1cKO mice exhibited more severe renal fibrosis in the UIRI model than wide-type littermates. Silencing XBP1 induced HK-2 cell cycle arrest in G2M phase, inhibited cell proliferation, and promoted TGF-β1 secretion. Proteomic analysis identified TNF receptor associated protein 1 (Trap1) as the potential downstream target transcriptionally regulated by XBP1s. Trap1 overexpression can alleviate silencing XBP1 induced profibrotic factor expressions and cell cycle arrest.
CONCLUSION: The loss of XBP1 in kidney injury was profibrotic, and the process was mediated by autocrine and paracrine regulations in combination. The present study identified the XBP1-Trap1 axis as an instrumental mechanism responsible for post-AKI fibrosis, which is a novel regulatory pathway.

Keywords:  Acute kidney injury; Chronic kidney disease; Fibrosis; Unfolded protein response; XBP1

DOI:  https://doi.org/10.1186/s12929-022-00828-9
Anal Chem. 2022 Jun 30.

Endoplasmic Reticulum-Targeting Near-Infrared Fluorescent Probe for CYP2J2 Activity and Its Imaging Application in Endoplasmic Reticulum Stress and Tumor.

Xiangge Tian, Tao Liu, Mingyue Zhu, Jiao Peng, Jingnan Cui, Lei Feng, Xiaokui Huo, Jinsong Yuan, Xiaochi Ma.

CYP2J2 as an endoplasmic reticulum (ER)-expressed vital cytochrome P450 isoform participates in the metabolism of endogenous polyunsaturated fatty acids. Its abnormal expression and function are closely related to the progress of cancer and cardiovascular diseases. Herein, an ER-targeting near-infrared (NIR) fluorescent probe ER-BnXPI was developed for monitoring CYP2J2 activity, which possessed a high selectivity and sensitivity toward CYP2J2 among various CYP450 isoforms and exhibited excellent subcellular localization for ER. Then, the CYP2J2 variation behavior under the ER stress model was imaged by ER-BnXPI in living cells and successfully used for the in vivo imaging in different tumors that well distinguished tumor tissues from para-cancerous tissues. All these findings fully demonstrated that ER-BnXPI could be used as a promising tool for exploring the physiological function of CYP2J2 and provided some novel approach for the diagnosis and therapy of CYP2J2-related vascular inflammation and cancer.

DOI: https://doi.org/10.1021/acs.analchem.2c00425