bims-unfpre 2024-01-14 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2024‒01‒14
eight papers selected by
Susan Logue, University of Manitoba

FBXO5-mediated RNF183 degradation prevents endoplasmic reticulum stress-induced apoptosis and promotes colon cancer progression.
Unveiling the Intercompartmental Signaling Axis: Mitochondrial to ER Stress Response (MERSR) and its Impact on Proteostasis.
Increased cellular protein modification by methylglyoxal activates endoplasmic reticulum-based sensors of the unfolded protein response.
Acute endoplasmic reticulum stress-induced mitochondria respiratory chain damage: The role of activated calpains.
Interleukin-38 alleviates hepatic steatosis through AMPK/autophagy-mediated suppression of endoplasmic reticulum stress in obesity models.
Palmitate induces integrated stress response and lipoapoptosis in trophoblasts.
CREB3L1/OASIS: cell cycle regulator and tumor suppressor.
miRNA-378 Is Downregulated by XBP1 and Inhibits Growth and Migration of Luminal Breast Cancer Cells.

Cell Death Dis. 2024 Jan 11. 15(1): 33

FBXO5-mediated RNF183 degradation prevents endoplasmic reticulum stress-induced apoptosis and promotes colon cancer progression.

Jing Ji, Aixin Jing, Yuanyuan Ding, Xinhui Ma, Qilan Qian, Ting Geng, Wenhao Cheng, Meiqi Zhang, Qian Sun, Shaojie Ma, Xiujun Wang, Qing Yuan, Menghan Xu, Jingting Qin, Lin Ma, Jiayan Yang, Jingliang He, Qianming Du, Mengbei Xia, Yuting Xu, Ziyun Chen, Lan Zhu, Wei Liu, Shunfang Liu, Bin Liu.

Endoplasmic reticulum (ER) stress induces the unfolded protein response (UPR), and prolonged ER stress leads to cell apoptosis. Despite increasing research in this area, the underlying molecular mechanisms remain unclear. Here, we discover that ER stress upregulates the UPR signaling pathway while downregulating E2F target gene expression and inhibiting the G2/M phase transition. Prolonged ER stress decreases the mRNA levels of E2F2, which specifically regulates the expression of F-Box Protein 5(FBXO5), an F-box protein that functions as an inhibitor of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase complex. Depletion of FBXO5 results in increased ER stress-induced apoptosis and decreased expression of proteins related to PERK/IRE1α/ATF6 signaling. Overexpression of FBXO5 wild-type (not its ΔF-box mutant) alleviates apoptosis and the expression of the C/EBP Homologous Protein (CHOP)/ATF. Mechanistically, we find that FBXO5 directly binds to and promotes the ubiquitin-dependent degradation of RNF183, which acts as a ubiquitin E3 ligase in regulating ER stress-induced apoptosis. Reversal of the apoptosis defects caused by FBXO5 deficiency in colorectal cancer cells can be achieved by knocking down RNF183 in FBXO5-deficient cells. Functionally, we observed significant upregulation of FBXO5 in colon cancer tissues, and its silencing suppresses tumor occurrence in vivo. Therefore, our study highlights the critical role of the FBXO5/RNF183 axis in ER stress regulation and identifies a potential therapeutic target for colon cancer treatment.

DOI: https://doi.org/10.1038/s41419-024-06421-2
bioRxiv. 2023 Dec 21. pii: 2023.09.07.556674. [Epub ahead of print]

Unveiling the Intercompartmental Signaling Axis: Mitochondrial to ER Stress Response (MERSR) and its Impact on Proteostasis.

Jeson J Li, Nan Xin, Chunxia Yang, Larissa A Tavizon, Ruth Hong, Travis I Moore, Rebecca George Tharyan, Adam Antebi, Hyun-Eui Kim.

Maintaining protein homeostasis is essential for cellular health. During times of proteotoxic stress, cells deploy unique defense mechanisms to achieve resolution. Our previous research uncovered a cross-compartmental Mitochondrial to Cytosolic Stress Response (MCSR), a unique stress response activated by the perturbation of mitochondrial proteostasis, which ultimately results in the improvement of proteostasis in the cytosol. Here, we found that this signaling axis also influences the unfolded protein response of the endoplasmic reticulum (UPR ER ), suggesting the presence of a Mitochondria to ER Stress Response (MERSR). During MERSR, the IRE1 branch of UPR ER is inhibited, introducing a previously unknown regulatory component of MCSR. Moreover, proteostasis is enhanced through the upregulation of the PERK-eIF2a signaling pathway, increasing phosphorylation of eIF2a and improving the ER's capacity to manage greater proteostasis load. MERSR activation in both poly-glutamine (poly-Q) and amyloid-beta (Aβ) C. elegans disease models also led to improvement in both aggregate burden and overall disease outcome. These findings shed light on the coordination between the mitochondria and the ER in maintaining cellular proteostasis and provides further evidence for the importance of intercompartmental signaling.

DOI: https://doi.org/10.1101/2023.09.07.556674
Redox Biol. 2024 Jan 05. pii: S2213-2317(24)00001-6. [Epub ahead of print]69 103025

Increased cellular protein modification by methylglyoxal activates endoplasmic reticulum-based sensors of the unfolded protein response.

Mingzhan Xue, Zehra Irshad, Naila Rabbani, Paul J Thornalley.

  The unfolded protein response (UPR) detects increased misfolded proteins and activates protein refolding, protein degradation and inflammatory responses. UPR sensors in the endoplasmic reticulum, IRE1α and PERK, bind and are activated by proteins with unexpected surface hydrophobicity, whereas sensor ATF6 is activated by proteolytic cleavage when released from complexation with protein disulfide isomerases (PDIs). Metabolic dysfunction leading to the formation of misfolded proteins with surface hydrophobicity and disruption of ATF6-PDI complexes leading to activation of UPR sensors remains unclear. The cellular concentration of reactive dicarbonyl metabolite, methylglyoxal (MG), is increased in impaired metabolic health, producing increased MG-modified cellular proteins. Herein we assessed the effect of high glucose concentration and related increased cellular MG on activation status of IRE1α, PERK and ATF6. Human aortal endothelial cells and HMEC-1 microvascular endothelial cells were incubated in low and high glucose concentration to model blood glucose control, with increase or decrease of MG by silencing or increasing expression of glyoxalase 1 (Glo1), which metabolizes MG. Increased MG induced by high glucose concentration activated IRE1α, PERK and ATF6 and related downstream signalling leading to increased chaperone, apoptotic and inflammatory gene expression. Correction of increased MG by increasing Glo1 expression prevented UPR activation. MG modification of proteins produces surface hydrophobicity through arginine-derived hydroimidazolone MG-H1 formation, with related protein unfolding and preferentially targets PDIs and chaperone pathways for modification. It thereby poses a major challenge to proteostasis and activates UPR sensors. Pharmacological decrease of MG with Glo1 inducer, trans-resveratrol and hesperetin in combination, offers a novel treatment strategy to counter UPR-related cell dysfunction, particularly in hyperglycemia associated with diabetes.

Keywords:  ER stress; Glycation; Glycemic disease; Hyperglycemia; Methylglyoxal; Unfolded protein response

DOI:  https://doi.org/10.1016/j.redox.2024.103025
FASEB J. 2024 Jan 31. 38(2): e23404

Acute endoplasmic reticulum stress-induced mitochondria respiratory chain damage: The role of activated calpains.

Qun Chen, Ling Li, Arun Samidurai, Jeremy Thompson, Ying Hu, Belinda Willard, Edward J Lesnefsky.

  The induction of acute endoplasmic reticulum (ER) stress damages the electron transport chain (ETC) in cardiac mitochondria. Activation of mitochondria-localized calpain 1 (CPN1) and calpain 2 (CPN2) impairs the ETC in pathological conditions, including aging and ischemia-reperfusion in settings where ER stress is increased. We asked if the activation of calpains causes the damage to the ETC during ER stress. Control littermate and CPNS1 (calpain small regulatory subunit 1) deletion mice were used in the current study. CPNS1 is an essential subunit required to maintain CPN1 and CPN2 activities, and deletion of CPNS1 prevents their activation. Tunicamycin (TUNI, 0.4 mg/kg) was used to induce ER stress in C57BL/6 mice. Cardiac mitochondria were isolated after 72 h of TUNI treatment. ER stress was increased in both control littermate and CPNS1 deletion mice with TUNI treatment. The TUNI treatment activated both cytosolic and mitochondrial CPN1 and 2 (CPN1/2) in control but not in CPNS1 deletion mice. TUNI treatment led to decreased oxidative phosphorylation and complex I activity in control but not in CPNS1 deletion mice compared to vehicle. The contents of complex I subunits, including NDUFV2 and ND5, were decreased in control but not in CPNS1 deletion mice. TUNI treatment also led to decreased oxidation through cytochrome oxidase (COX) only in control mice. Proteomic study showed that subunit 2 of COX was decreased in control but not in CPNS1 deletion mice. Our results provide a direct link between activation of CPN1/2 and complex I and COX damage during acute ER stress.

Keywords:  calpain 1; calpain 2; complex I; cytochrome oxidase; tunicamycin

DOI:  https://doi.org/10.1096/fj.202301158RR
J Cell Physiol. 2024 Jan 10.

Interleukin-38 alleviates hepatic steatosis through AMPK/autophagy-mediated suppression of endoplasmic reticulum stress in obesity models.

Jaw Long Sun, Wonjun Cho, Heeseung Oh, A M Abd El-Aty, Soon Auck Hong, Ji Hoon Jeong, Tae Woo Jung.

  Interleukin-38 (IL-38), recently recognized as a cytokine with anti-inflammatory properties that mitigate type 2 diabetes, has been associated with indicators of insulin resistance and nonalcoholic fatty liver disease (NAFLD). This study investigated the impact of IL-38 on hepatic lipid metabolism and endoplasmic reticulum (ER) stress. We assessed protein expression levels using Western blot analysis, while monodansylcadaverine staining was employed to detect autophagosomes in hepatocytes. Oil red O staining was utilized to examine lipid deposition. The study revealed elevated serum IL-38 levels in high-fat diet (HFD)-fed mice and IL-38 secretion from mouse keratinocytes. IL-38 treatment attenuated lipogenic lipid accumulation and ER stress markers in hepatocytes exposed to palmitate. Furthermore, IL-38 treatment increased AMP-activated protein kinase (AMPK) phosphorylation and autophagy. The effects of IL-38 on lipogenic lipid deposition and ER stress were nullified in cultured hepatocytes by suppressing AMPK through small interfering (si) RNA or 3-methyladenine (3MA). In animal studies, IL-38 administration mitigated hepatic steatosis by suppressing the expression of lipogenic proteins and ER stress markers while reversing AMPK phosphorylation and autophagy markers in the livers of HFD-fed mice. Additionally, AMPK siRNA, but not 3MA, mitigated IL-38-enhanced fatty acid oxidation in hepatocytes. In summary, IL-38 alleviates hepatic steatosis through AMPK/autophagy signaling-dependent attenuation of ER stress and enhancement of fatty acid oxidation via the AMPK pathway, suggesting a therapeutic strategy for treating NAFLD.

Keywords:  AMP-activated protein kinase; IL-38; autophagy; endoplasmic reticulum stress; hepatic steatosis; obesity

DOI:  https://doi.org/10.1002/jcp.31184
Cell Death Dis. 2024 Jan 11. 15(1): 31

Palmitate induces integrated stress response and lipoapoptosis in trophoblasts.

Prakash Kumar Sahoo, Chandan Krishnamoorthy, Jennifer R Wood, Corrine Hanson, Ann Anderson-Berry, Justin L Mott, Sathish Kumar Natarajan.

Maternal obesity increases the risk of childhood obesity and programs the offspring to develop metabolic syndrome later in their life. Palmitate is the predominant saturated free fatty acid (FFA) that is transported across the placenta to the fetus. We have recently shown that saturated FFA in the maternal circulation as a result of increased adipose tissue lipolysis in third trimester of pregnancy induces trophoblast lipoapoptosis. Here, we hypothesized that palmitate induces integrated stress response by activating mitogen-activated protein kinases (MAPKs), endoplasmic reticulum (ER) stress and granular stress and lipoapoptosis in trophoblasts. Choriocarcinoma-derived third-trimester placental trophoblast-like cells (JEG-3 and JAR) referred as trophoblasts were exposed to various concentrations of palmitate (PA). Apoptosis was assessed by nuclear morphological changes and caspase 3/7 activity. Immunoblot and immunofluorescence analysis was performed to measure the activation of MAPKs, ER stress and granular stress response pathways. Trophoblasts exposed to pathophysiological concentrations of PA showed a concentration-dependent increase in trophoblast lipoapoptosis. PA induces a caspase-dependent trophoblast lipoapoptosis. Further, PA induces MAPK activation (JNK and ERK) via phosphorylation, and activation of ER stress as evidenced by an increased phosphorylation eIF2α & IRE1α. PA also induces the activation of stress granules formation. Two pro-apoptotic transcriptional mediators of PA-induced trophoblast lipoapoptosis, CHOP and FoxO3 have increased nuclear translocation. Mechanistically, PA-induced JNK is critical for trophoblast lipoapoptosis. However, PA-induced activation of ERK and stress granule formation were shown to be cell survival signals to combat subcellular stress due to PA exposure. In conclusion, PA induces the activation of integrated stress responses, among which small molecule inhibition of JNK demonstrated that activation of JNK is critical for PA-induced trophoblast lipoapoptosis and small molecule activation of stress granule formation significantly prevents PA-induced trophoblast lipoapoptosis.

DOI: https://doi.org/10.1038/s41419-023-06415-6
FEBS J. 2024 Jan 12.

CREB3L1/OASIS: cell cycle regulator and tumor suppressor.

Atsushi Saito, Issei Omura, Kazunori Imaizumi.

  Cell cycle checkpoints detect DNA errors, eventually arresting the cell cycle to promote DNA repair. Failure of such cell cycle arrest causes aberrant cell proliferation, promoting the pathogenesis of multiple diseases, including cancer. Endoplasmic reticulum (ER) stress transducers activate the unfolded protein response, which not only deals with unfolded proteins in ER lumen but also orchestrates diverse physiological phenomena such as cell differentiation and lipid metabolism. Among ER stress transducers, cyclic AMP-responsive element-binding protein 3-like protein 1 (CREB3L1) [also known as old astrocyte specifically induced substance (OASIS)] is an ER-resident transmembrane transcription factor. This molecule is cleaved by regulated intramembrane proteolysis, followed by activation as a transcription factor. OASIS is preferentially expressed in specific cells, including astrocytes and osteoblasts, to regulate their differentiation. In accordance with its name, OASIS was originally identified as being upregulated in long-term-cultured astrocytes undergoing cell cycle arrest because of replicative stress. In the context of cell cycle regulation, previously unknown physiological roles of OASIS have been discovered. OASIS is activated as a transcription factor in response to DNA damage to induce p21-mediated cell cycle arrest. Although p21 is directly induced by the master regulator of the cell cycle, p53, no crosstalk occurs between p21 induction by OASIS or p53. Here, we summarize previously unknown cell cycle regulation by ER-resident transcription factor OASIS, particularly focusing on commonalities and differences in cell cycle arrest between OASIS and p53. This review also mentions tumorigenesis caused by OASIS dysfunctions, and OASIS's potential as a tumor suppressor and therapeutic target.

Keywords:  DNA damage; OASIS; astrocyte; cell cycle arrest; glioblastoma; methylation; p21; p53; tumor suppressor; tumorigenesis

DOI:  https://doi.org/10.1111/febs.17052
Int J Mol Sci. 2023 Dec 22. pii: 186. [Epub ahead of print]25(1):

miRNA-378 Is Downregulated by XBP1 and Inhibits Growth and Migration of Luminal Breast Cancer Cells.

Vahid Arabkari, David Barua, Muhammad Mosaraf Hossain, Mark Webber, Terry Smith, Ananya Gupta, Sanjeev Gupta.

  X-box binding protein 1 (XBP1) is a transcription factor that plays a crucial role in the unfolded protein response (UPR), a cellular stress response pathway involved in maintaining protein homeostasis in the endoplasmic reticulum (EnR). While the role of XBP1 in UPR is well-characterised, emerging evidence suggests its involvement in endocrine resistance in breast cancer. The transcriptional activity of spliced XBP1 (XBP1s) is a major component of its biological effects, but the targets of XBP1s in estrogen receptor (ER)-positive breast cancer are not well understood. Here, we show that the expression of miR-378 and PPARGC1B (host gene of miR-378) is downregulated during UPR. Using chemical and genetic methods, we show that XBP1s is necessary and sufficient for the downregulation of miR-378 and PPARGC1B. Our results show that overexpression of miR-378 significantly suppressed cell growth, colony formation, and migration of ER-positive breast cancer cells. Further, we found that expression of miR-378 sensitised the cells to UPR-induced cell death and anti-estrogens. The expression of miR-378 and PPARGC1B was downregulated in breast cancer, and higher expression of miR-378 is associated with better outcomes in ER-positive breast cancer. We found that miR-378 upregulates the expression of several genes that regulate type I interferon signalling. Analysis of separate cohorts of breast cancer patients showed that a gene signature derived from miR-378 upregulated genes showed a strong association with improved overall and recurrence-free survival in breast cancer. Our results suggest a growth-suppressive role for miR-378 in ER-positive breast cancer where downregulation of miR-378 by XBP1 contributes to endocrine resistance in ER-positive breast cancer.

Keywords:  XBP1; breast cancer; endocrine resistance; endoplasmic reticulum stress; miR-378; unfolded protein response

DOI:  https://doi.org/10.3390/ijms25010186