bims-unfpre 2021-06-27 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2021–06–27
ten papers selected by
Susan Logue, University of Manitoba

N-glycan processing selects ERAD-resistant misfolded proteins for ER-to-lysosome-associated degradation.
Hepatic X-box binding protein 1 and unfolded protein response is impaired in weanling mice with resultant hepatic injury.
The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity.
Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus.
Induction of EnR stress by Melatonin enhances the cytotoxic effect of Lapatinib in HER2-positive breast cancer.
The Cross-Links of Endoplasmic Reticulum Stress, Autophagy, and Neurodegeneration in Parkinson's Disease.
Serum X-box-binding protein 1 levels in PCOS patients.
Western diet leads to aging-related tumorigenesis via activation of the inflammatory, UPR, and EMT pathways.
Thbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy.
lncRNA MALAT1 participates in metformin inhibiting the proliferation of breast cancer cell.

EMBO J. 2021 Jun 21. e107240

N-glycan processing selects ERAD-resistant misfolded proteins for ER-to-lysosome-associated degradation.

Ilaria Fregno, Elisa Fasana, Tatiana Soldà, Carmela Galli, Maurizio Molinari.

  Efficient degradation of by-products of protein biogenesis maintains cellular fitness. Strikingly, the major biosynthetic compartment in eukaryotic cells, the endoplasmic reticulum (ER), lacks degradative machineries. Misfolded proteins in the ER are translocated to the cytosol for proteasomal degradation via ER-associated degradation (ERAD). Alternatively, they are segregated in ER subdomains that are shed from the biosynthetic compartment and are delivered to endolysosomes under control of ER-phagy receptors for ER-to-lysosome-associated degradation (ERLAD). Demannosylation of N-linked oligosaccharides targets terminally misfolded proteins for ERAD. How misfolded proteins are eventually marked for ERLAD is not known. Here, we show for ATZ and mutant Pro-collagen that cycles of de-/re-glucosylation of selected N-glycans and persistent association with Calnexin (CNX) are required and sufficient to mark ERAD-resistant misfolded proteins for FAM134B-driven lysosomal delivery. In summary, we show that mannose and glucose processing of N-glycans are triggering events that target misfolded proteins in the ER to proteasomal (ERAD) and lysosomal (ERLAD) clearance, respectively, regulating protein quality control in eukaryotic cells.

Keywords:  ER-phagy; ERAD; ERLAD; N-glycan processing; Protein quality control

DOI:  https://doi.org/10.15252/embj.2020107240
Hepatology. 2021 Jun 25.

Hepatic X-box binding protein 1 and unfolded protein response is impaired in weanling mice with resultant hepatic injury.

Alyssa Kriegermeier, Angela Hyon, Meredith Sommars, Susan Hubchak, Brian LeCuyer, Xiaoying Liu, Grant Barish, Richard M Green.

   BACKGROUND & AIMS: The unfolded protein response (UPR) is a coordinated cellular response to endoplasmic reticulum (ER) stress that functions to maintain cellular homeostasis. When ER stress is unresolved, the UPR can trigger apoptosis. Pathways within the UPR influence bile acid metabolism in adult animal models and adult human liver diseases, however the UPR has not been studied in young animal models or pediatric liver diseases. In this study we sought to determine if weanling age mice had altered UPR activation compared to adult mice which could lead to increased bile acid induced hepatic injury APPROACH & RESULTS: We demonstrate that after 7 days of cholic acid (CA) feeding to wild type (WT) animals, weanling age mice have a 2-fold greater serum ALT levels compared to adult mice, with increased hepatic apoptosis. Weanling mice fed CA have increased hepatic nuclear X-box binding protein 1 spliced (XBP1s) expression, but cannot increase expression of its protective downstream targets endoplasmic reticulum DNA J domain-containing protein 4 (ERdj4) and ER degradation enhancing α-mannoside (EDEM). In response to tunicamycin induced ER stress, young mice have blunted expression of several UPR pathways compared to adult mice. CA feeding to adult liver-specific XBP1 knockout (LS-XBP1-/- ) mice, which are unable to resolve hepatic ER stress, leads to increased serum ALT and C/EBP homologous protein (CHOP), a proapoptotic UPR molecule, expression to levels similar to CA fed LS-XBP1-/- weanlings.
CONCLUSIONS: Weanling mice have attenuated hepatic XBP1 signaling and impaired UPR activation with resultant increased susceptibility to bile acid induced injury.

Keywords:  ER stress; bile acid; cholestasis; endoplasmic reticulum; liver

DOI:  https://doi.org/10.1002/hep.32031
Sci Rep. 2021 Jun 22. 11(1): 13086

The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity.

Dinh Thi Nguyen, Thuong Manh Le, Tsuyoshi Hattori, Mika Takarada-Iemata, Hiroshi Ishii, Jureepon Roboon, Takashi Tamatani, Takayuki Kannon, Kazuyoshi Hosomichi, Atsushi Tajima, Shusuke Taniuchi, Masato Miyake, Seiichi Oyadomari, Takashi Tanaka, Nobuo Kato, Shunsuke Saito, Kazutoshi Mori, Osamu Hori.

While ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of its paralogue ATF6β remains elusive, especially in the central nervous system (CNS). Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin (CRT), a molecular chaperone in the ER with a high Ca2+-binding capacity. CRT expression was reduced to ~ 50% in the CNS of Atf6b-/- mice under both normal and ER stress conditions. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death. The higher levels of death in Atf6b-/- neurons were recovered by ATF6β and CRT overexpressions, or by treatment with Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and with an ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in the hippocampi of Atf6b-/- and Calr+/- mice, and restored by administration of 2-APB and salubrinal. These results suggest that the ATF6β-CRT axis promotes neuronal survival under ER stress and excitotoxity by improving intracellular Ca2+ homeostasis.

DOI: https://doi.org/10.1038/s41598-021-92529-w
Nat Rev Endocrinol. 2021 Jun 23.

Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus.

Jing Yong, James D Johnson, Peter Arvan, Jaeseok Han, Randal J Kaufman.

Diabetes mellitus is characterized by the failure of insulin-secreting pancreatic β-cells (or β-cell death) due to either autoimmunity (type 1 diabetes mellitus) or failure to compensate for insulin resistance (type 2 diabetes mellitus; T2DM). In addition, mutations of critical genes cause monogenic diabetes. The endoplasmic reticulum (ER) is the primary site for proinsulin folding; therefore, ER proteostasis is crucial for both β-cell function and survival under physiological and pathophysiological challenges. Importantly, the ER is also the major intracellular Ca2+ storage organelle, generating Ca2+ signals that contribute to insulin secretion. ER stress is associated with the pathogenesis of diabetes mellitus. In this Review, we summarize the mutations in monogenic diabetes that play causal roles in promoting ER stress in β-cells. Furthermore, we discuss the possible mechanisms responsible for ER proteostasis imbalance with a focus on T2DM, in which both genetics and environment are considered important in promoting ER stress in β-cells. We also suggest that controlled insulin secretion from β-cells might reduce the progression of a key aspect of the metabolic syndrome, namely nonalcoholic fatty liver disease. Finally, we evaluate potential therapeutic approaches to treat T2DM, including the optimization and protection of functional β-cell mass in individuals with T2DM.

DOI: https://doi.org/10.1038/s41574-021-00510-4
Cancer Lett. 2021 Jun 18. pii: S0304-3835(21)00296-2. [Epub ahead of print]518 82-93

Induction of EnR stress by Melatonin enhances the cytotoxic effect of Lapatinib in HER2-positive breast cancer.

Xiaolin Sang, Li Li, Chunhua Rui, Yichao Liu, Zundong Liu, Zhiwei Tao, Hailing Cheng, Pixu Liu.

  Despite HER2-targeted cancer treatments have provided considerable clinical benefits, resistance to HER2-targeted agents will inevitably develop. Targeting non-oncogene vulnerabilities including endoplasmic reticulum (EnR) stress has emerged as an attractive alternative approach to improve the efficacy of existing targeted cancer therapies. In the current study, we find that Melatonin sensitizes HER2-positive breast cancer cells to the dual tyrosine kinase inhibitor Lapatinib in vitro. Mechanistically, Melatonin enhances the cytotoxic effects of Lapatinib through promoting excessive EnR stress-induced unfolded protein response (UPR) and ROS overaccumulation. Consistently, the antioxidant N-acetylcysteine remarkably reverses the effects of the drug combination on ROS production, DNA damage and cytotoxicity. Furthermore, Melatonin significantly enhances the anti-tumor effect of Lapatinib in an HCC1954 xenograft model. Meanwhile, Lapatinib resistant HER2-positive breast cancer cells (LapR) display lower basal expression levels of UPR genes and enhanced tolerance to EnR stress with attenuated response to Brefeldin A and Tunicamycin. Importantly, Melatonin also increases the sensitivity of HCC1954 LapR cells to Lapatinib. Together, our findings highlight the potential utility of Melatonin as an adjuvant in the treatment of primary or therapy resistant HER2-positive breast cancer via EnR stress-mediated mechanisms.

Keywords:  Breast cancer; EnR stress; HER2 targeted therapy; Lapatinib resistance; ROS

DOI:  https://doi.org/10.1016/j.canlet.2021.06.011
Front Aging Neurosci. 2021 ;13 691881

The Cross-Links of Endoplasmic Reticulum Stress, Autophagy, and Neurodegeneration in Parkinson's Disease.

Haigang Ren, Wanqing Zhai, Xiaojun Lu, Guanghui Wang.

  Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and it is characterized by the selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), as well as the presence of intracellular inclusions with α-synuclein as the main component in surviving DA neurons. Emerging evidence suggests that the imbalance of proteostasis is a key pathogenic factor for PD. Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and autophagy, two major pathways for maintaining proteostasis, play important roles in PD pathology and are considered as attractive therapeutic targets for PD treatment. However, although ER stress/UPR and autophagy appear to be independent cellular processes, they are closely related to each other. In this review, we focused on the roles and molecular cross-links between ER stress/UPR and autophagy in PD pathology. We systematically reviewed and summarized the most recent advances in regulation of ER stress/UPR and autophagy, and their cross-linking mechanisms. We also reviewed and discussed the mechanisms of the coexisting ER stress/UPR activation and dysregulated autophagy in the lesion regions of PD patients, and the underlying roles and molecular crosslinks between ER stress/UPR activation and the dysregulated autophagy in DA neurodegeneration induced by PD-associated genetic factors and PD-related neurotoxins. Finally, we indicate that the combined regulation of ER stress/UPR and autophagy would be a more effective treatment for PD rather than regulating one of these conditions alone.

Keywords:  ER stress; Parkinson’s disease; UPR; autophagy; cross-link; α-synuclein

DOI:  https://doi.org/10.3389/fnagi.2021.691881
Gynecol Endocrinol. 2021 Jun 23. 1-5

Serum X-box-binding protein 1 levels in PCOS patients.

Ece Bahçeci, Cihan Kaya, Sema Karakaş, Şükrü Yıldız, Murat Hoşgören, Murat Ekin.

   OBJECTIVE: X-box binding protein-1 (XBP1) is a possible indicator of metabolic syndrome and diabetes. This study aimed to evaluate the relationship between serum XBP1 levels and polycystic ovary syndrome (PCOS).
METHOD: A prospective observational study was conducted with 88 patients. The first group was defined as the control group with ovulatory and normal-BMI patients (n = 28). The second group comprised of nonobese PCOS patients (n = 30). The third group included overweight/obese patients with PCOS (n = 30). Fasting plasma glucose, serum lipids, follicle stimulating hormone, luteinizing hormone, total testosterone, dehydroepiandrosterone and XBP1 levels l were evaluated in all groups.
RESULTS: There was a significant difference in XBP1 levels between the study groups, and higher levels were observed both in the nonobese and obese PCOS groups than in the healthy controls (p < .001). The median level of XBP1 was 73.7 pg/ml in the control group, 114.11 pg/ml in the nonobese PCOS group, and 151.61 pg/ml in the overweight/obese PCOS group. A cutoff level of XBP1 at 95.79 pg/ml level was determined with a significant AUC (area under the curve) level of 99% and high specificity and sensitivity rates to predict PCOS. Also, a significant positive correlation was observed between XBP1 levels and BMI, waist circumference, fasting plasma glucose and triglyceride levels (p < .05).
CONCLUSIONS: XBP1 levels were significantly higher in PCOS patients, particularly in overweight/obese PCOS patients, than in the controls. Also, the parameters associated with metabolic syndrome were related to XBP1 levels.

Keywords:  ER stress; Polycystic ovary syndrome; X-box protein 1; insulin resistance

DOI:  https://doi.org/10.1080/09513590.2021.1942449
Cell Death Dis. 2021 Jun 23. 12(7): 643

Western diet leads to aging-related tumorigenesis via activation of the inflammatory, UPR, and EMT pathways.

Ricardo Imbroisi Filho, Alan C Ochioni, Amanda M Esteves, João G B Leandro, Thainá M Demaria, Mauro Sola-Penna, Patricia Zancan.

Among the principal causative factors for the development of complications related to aging is a diet rich in fats and sugars, also known as the Western diet. This diet advocates numerous changes that might increase the susceptibility to initiate cancer and/or to create a tissue microenvironment more conducive to the growth of malignant cells, thus favoring the progression of cancer and metastasis. Hypercaloric diets in general lead to oxidative stress generating reactive oxygen species and induce endoplasmic reticulum stress. Our results demonstrate that mice bearing tumors fed with a Western diet presented bigger tumor mass with increased insulin sensitivity in these tissues. Several markers of insulin signaling, such as AKT phosphorylation and mTOR pathway, are promoted in tumors of Western diet-fed animals. This process is associated with increased macrophage infiltration, activation of unfolded protein response pathway, and initiation of epithelial-mesenchymal transition (EMT) process in these tumor tissues. Summing up, we propose that the Western diet accelerates the aging-related processes favoring tumor development.

DOI: https://doi.org/10.1038/s41419-021-03929-9
Nat Commun. 2021 06 24. 12(1): 3928

Thbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy.

Davy Vanhoutte, Tobias G Schips, Alexander Vo, Kelly M Grimes, Tanya A Baldwin, Matthew J Brody, Federica Accornero, Michelle A Sargent, Jeffery D Molkentin.

The thrombospondin (Thbs) family of secreted matricellular proteins are stress- and injury-induced mediators of cellular attachment dynamics and extracellular matrix protein production. Here we show that Thbs1, but not Thbs2, Thbs3 or Thbs4, induces lethal cardiac atrophy when overexpressed. Mechanistically, Thbs1 binds and activates the endoplasmic reticulum stress effector PERK, inducing its downstream transcription factor ATF4 and causing lethal autophagy-mediated cardiac atrophy. Antithetically, Thbs1-/- mice develop greater cardiac hypertrophy with pressure overload stimulation and show reduced fasting-induced atrophy. Deletion of Thbs1 effectors/receptors, including ATF6α, CD36 or CD47 does not diminish Thbs1-dependent cardiac atrophy. However, deletion of the gene encoding PERK in Thbs1 transgenic mice blunts the induction of ATF4 and autophagy, and largely corrects the lethal cardiac atrophy. Finally, overexpression of PERK or ATF4 using AAV9 gene-transfer similarly promotes cardiac atrophy and lethality. Hence, we identified Thbs1-mediated PERK-eIF2α-ATF4-induced autophagy as a critical regulator of cardiomyocyte size in the stressed heart.

DOI: https://doi.org/10.1038/s41467-021-24215-4
J Cell Mol Med. 2021 Jun 24.

lncRNA MALAT1 participates in metformin inhibiting the proliferation of breast cancer cell.

Yongye Huang, Ziyan Zhou, Jin Zhang, Zhenzhen Hao, Yunhao He, Zihan Wu, Yiquan Song, Kexun Yuan, Shanyu Zheng, Qi Zhao, Tianye Li, Bing Wang.

  In recent years, the repurposing of conventional and chemotherapeutic drugs is recognized as an alternative strategy for health care. The main purpose of this study is to strengthen the application of non-oncological drug metformin on breast cancer treatment in the perspective of epigenetics. In the present study, metformin was found to inhibit cell proliferation, promote apoptosis and induce cell cycle arrest in breast cancer cells at a dose-dependent manner. In addition, metformin treatment elevated acH3K9 abundance and decreased acH3K18 level. The expression of lncRNA MALAT1, HOTAIR, DICER1-AS1, LINC01121 and TUG1 was up-regulated by metformin treatment. In metformin-treated cells, MALAT1 knock-down increased the Bax/Bcl2 ratio and enhanced p21 but decreased cyclin B1 expression. The expression of Beclin1, VDAC1, LC3-II, CHOP and Bip was promoted in the cells received combinatorial treatment of metformin and MALAT1 knock-down. The reduced phosphorylation of c-Myc was further decreased in the metformin-treated cells in combination with MALAT1 knock-down than metformin treatment alone. Taken together, these results provide a promising repurposed strategy for metformin on cancer treatment by modulating epigenetic modifiers.

Keywords:  ER stress; MALAT1; autophagy; metformin

DOI:  https://doi.org/10.1111/jcmm.16742