bims-unfpre 2022-01-30 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2022‒01‒30
eight papers selected by
Susan Logue
University of Manitoba

Adaptation to Endoplasmic Reticulum Stress in Candida albicans Relies on the Activity of the Hog1 Mitogen-Activated Protein Kinase.
Induction and Aggravation of the Endoplasmic-Reticulum Stress by Membrane-Lipid Metabolic Intermediate Phosphatidyl-N-Monomethylethanolamine.
ER-stress promotes VHL-independent degradation of hypoxia-inducible factors via FBXW1A/βTrCP.
ER stress-induced cell death proceeds independently of the TRAIL-R2 signaling axis in pancreatic β cells.
Endoplasmic Reticulum Stress-Associated Neuronal Death and Innate Immune Response in Neurological Diseases.
Clusterin is involved in mediating the metabolic function of adipose SIRT1.
ATF6α promotes prostate cancer progression by enhancing PLA2G4A-mediated arachidonic acid metabolism and protecting tumor cells against ferroptosis.
Reductive stress triggers ANAC017-mediated retrograde signaling to safeguard the endoplasmic reticulum by boosting mitochondrial respiratory capacity.

Front Microbiol. 2021 ;12 794855

Adaptation to Endoplasmic Reticulum Stress in Candida albicans Relies on the Activity of the Hog1 Mitogen-Activated Protein Kinase.

Farha Husain, Prerna Pathak, Elvira Román, Jesús Pla, Sneh Lata Panwar.

  Adaptation to ER stress is linked to the pathogenicity of C. albicans. The fungus responds to ER stress primarily by activating the conserved Ire1-Hac1-dependent unfolded protein response (UPR) pathway. Subsequently, when ER homeostasis is re-established, the UPR is attenuated in a timely manner, a facet that is unexplored in C. albicans. Here, we show that C. albicans licenses the HOG (high-osmolarity glycerol) MAPK pathway for abating ER stress as evidenced by activation and translocation of Hog1 to the nucleus during tunicamycin-induced ER stress. We find that, once activated, Hog1 attenuates the activity of Ire1-dependent UPR, thus facilitating adaptation to ER stress. We use the previously established assay, where the disappearance of the UPR-induced spliced HAC1 mRNA correlates with the re-establishment of ER homeostasis, to investigate attenuation of the UPR in C. albicans. hog1Δ/Δ cells retain spliced HAC1 mRNA levels for longer duration reflecting the delay in attenuating Ire1-dependent UPR. Conversely, compromising the expression of Ire1 (ire1 DX mutant strain) results in diminished levels of phosphorylated Hog1, restating the cross-talk between Ire1 and HOG pathways. Phosphorylation signal to Hog1 MAP kinase is relayed through Ssk1 in response to ER stress as inactivation of Ssk1 abrogates Hog1 phosphorylation in C. albicans. Additionally, Hog1 depends on its cytosolic as well as nuclear activity for mediating ER stress-specific responses in the fungus. Our results show that HOG pathway serves as a point of cross-talk with the UPR pathway, thus extending the role of this signaling pathway in promoting adaptation to ER stress in C. albicans. Additionally, this study integrates this MAPK pathway into the little known frame of ER stress adaptation pathways in C. albicans.

Keywords:  Candida; HOG MAPK; Hac1; Ire1; endoplasmic reticulum stress; tunicamycin; unfolded protein response

DOI:  https://doi.org/10.3389/fmicb.2021.794855
Front Cell Dev Biol. 2021 ;9 743018

Induction and Aggravation of the Endoplasmic-Reticulum Stress by Membrane-Lipid Metabolic Intermediate Phosphatidyl-N-Monomethylethanolamine.

Yuki Ishiwata-Kimata, Quynh Giang Le, Yukio Kimata.

  Phosphatidylcholine (PC) is produced via two distinct pathways in both hepatocytes and yeast, Saccharomyces cerevisiae. One of these pathways involves the sequential methylation of phosphatidylethanolamine (PE). In yeast cells, the methyltransferase, Cho2, converts PE to phosphatidylmonomethylethanolamine (PMME), which is further modified to PC by another methyltransferase, Opi3. On the other hand, free choline is utilized for PC production via the Kennedy pathway. The blockage of PC production is well known to cause endoplasmic reticulum (ER) stress and activate the ER-stress sensor, Ire1, to induce unfolded protein response (UPR). Here, we demonstrate that even when free choline is sufficiently supplied, the opi3Δ mutation, but not the cho2 Δ mutation, induces the UPR. The UPR was also found to be induced by CHO2 overexpression. Further, monomethylethanolamine, which is converted to PMME probably through the Kennedy pathway, caused or potentiated ER stress in both mammalian and yeast cells. We thus deduce that PMME per se is an ER-stressing molecule. Interestingly, spontaneously accumulated PMME seemed to aggravate ER stress in yeast cells. Collectively, our findings demonstrate the multiple detrimental effects of the low-abundance phospholipid species, PMME.

Keywords:  endoplasmic reticulum; membrane; phospholipids; unfolded protein response; yeast

DOI:  https://doi.org/10.3389/fcell.2021.743018
Redox Biol. 2022 Jan 18. pii: S2213-2317(22)00015-5. [Epub ahead of print]50 102243

ER-stress promotes VHL-independent degradation of hypoxia-inducible factors via FBXW1A/βTrCP.

Daniela Mennerich, Kateryna Kubaichuk, Ghulam S Raza, Dominik C Fuhrmann, Karl-Heinz Herzig, Bernhard Brüne, Thomas Kietzmann.

  Metabolic adaptation and signal integration in response to hypoxic conditions is mainly regulated by hypoxia-inducible factors (HIFs). At the same time, hypoxia induces ROS formation and activates the unfolded protein response (UPR), indicative of endoplasmic reticulum (ER) stress. However, whether ER stress would affect the hypoxia response remains ill-defined. Here we report that feeding mice a high fat diet causes ER stress and attenuates the response to hypoxia. Mechanistically, ER stress promotes HIF-1α and HIF-2α degradation independent of ROS, Ca2+, and the von Hippel-Lindau (VHL) pathway, involving GSK3β and the ubiquitin ligase FBXW1A/βTrCP. Thereby, we reveal a previously unknown function of the GSK3β/HIFα/βTrCP1 axis in ER homeostasis and demonstrate that inhibition of the HIF-1 and HIF-2 response and genetic deficiency of GSK3β affects proliferation, migration, and sensitizes cells for ER stress promoted apoptosis. Vice versa, we show that hypoxia affects the ER stress response mainly through the PERK-arm of the UPR. Overall, we discovered previously unrecognized links between the HIF pathway and the ER stress response and uncovered an essential survival pathway for cells under ER stress.

Keywords:  ER stress; HIF-1α; HIF-2α; Mild hypoxia; UPR

DOI:  https://doi.org/10.1016/j.redox.2022.102243
Cell Death Discov. 2022 Jan 24. 8(1): 34

ER stress-induced cell death proceeds independently of the TRAIL-R2 signaling axis in pancreatic β cells.

Cathrin Hagenlocher, Robin Siebert, Bruno Taschke, Senait Wieske, Angelika Hausser, Markus Rehm.

Prolonged ER stress and the associated unfolded protein response (UPR) can trigger programmed cell death. Studies in cancer cell lines demonstrated that the intracellular accumulation of TRAIL receptor-2 (TRAIL-R2) and the subsequent activation of caspase-8 contribute significantly to apoptosis induction upon ER stress. While this might motivate therapeutic strategies that promote cancer cell death through ER stress-induced caspase-8 activation, it could also support the unwanted demise of non-cancer cells. Here, we therefore investigated if TRAIL-R2 dependent signaling towards apoptosis can be induced in pancreatic β cells, whose loss by prolonged ER stress is associated with the onset of diabetes. Interestingly, we found that elevated ER stress in these cells does not result in TRAIL-R2 transcriptional induction or elevated protein levels, and that the barely detectable expression of TRAIL-R2 is insufficient to allow TRAIL-induced apoptosis to proceed. Overall, this indicates that apoptotic cell death upon ER stress most likely proceeds independent of TRAIL-R2 in pancreatic β cells. Our findings therefore point to differences in ER stress response and death decision-making between cancer cells and pancreatic β cells and also have implications for future targeted treatment strategies that need to differentiate between ER stress susceptibility of cancer cells and pancreatic β cells.

DOI: https://doi.org/10.1038/s41420-022-00830-y
Front Immunol. 2021 ;12 794580

Endoplasmic Reticulum Stress-Associated Neuronal Death and Innate Immune Response in Neurological Diseases.

Mingming Shi, Yan Chai, Jianning Zhang, Xin Chen.

  Neuronal death and inflammatory response are two common pathological hallmarks of acute central nervous system injury and chronic degenerative disorders, both of which are closely related to cognitive and motor dysfunction associated with various neurological diseases. Neurological diseases are highly heterogeneous; however, they share a common pathogenesis, that is, the aberrant accumulation of misfolded/unfolded proteins within the endoplasmic reticulum (ER). Fortunately, the cell has intrinsic quality control mechanisms to maintain the proteostasis network, such as chaperone-mediated folding and ER-associated degradation. However, when these control mechanisms fail, misfolded/unfolded proteins accumulate in the ER lumen and contribute to ER stress. ER stress has been implicated in nearly all neurological diseases. ER stress initiates the unfolded protein response to restore proteostasis, and if the damage is irreversible, it elicits intracellular cascades of death and inflammation. With the growing appreciation of a functional association between ER stress and neurological diseases and with the improved understanding of the multiple underlying molecular mechanisms, pharmacological and genetic targeting of ER stress are beginning to emerge as therapeutic approaches for neurological diseases.

Keywords:  endoplasmic reticulum stress; inflammatory response; neurological diseases; neuronal death; proteostasis; unfolded protein response

DOI:  https://doi.org/10.3389/fimmu.2021.794580
iScience. 2022 Jan 21. 25(1): 103709

Clusterin is involved in mediating the metabolic function of adipose SIRT1.

Pengcheng Zhang, Daniels Konja, Yiwei Zhang, Aimin Xu, In-Kyu Lee, Jae-Han Jeon, Ghader Bashiri, Alok Mitra, Yu Wang.

  SIRT1 is a metabolic sensor regulating energy homeostasis. The present study revealed that mice with selective overexpression of human SIRT1 in adipose tissue (Adipo-SIRT1) were protected from high-fat diet (HFD)-induced metabolic abnormalities. Adipose SIRT1 was enriched at mitochondria-ER contacts (MERCs) to trigger mitohormesis and unfolded protein response (UPRmt), in turn preventing ER stress. As a downstream target of UPRmt, clusterin was significantly upregulated and acted together with SIRT1 to regulate the protein and lipid compositions at MERCs of adipose tissue. In mice lacking clusterin, HFD-induced metabolic abnormalities were significantly enhanced and could not be prevented by overexpression of SIRT1 in adipose tissue. Treatment with ER stress inhibitors restored adipose SIRT1-mediated beneficial effects on systemic energy metabolism. In summary, adipose SIRT1 facilitated the dynamic interactions and communications between mitochondria and ER, via MERCs, in turn triggering a mild mitochondrial stress to instigate the defense responses against dietary obesity-induced metabolic dysfunctions.

Keywords:  Biological sciences; Cell biology; Molecular physiology

DOI:  https://doi.org/10.1016/j.isci.2021.103709
Prostate. 2022 Jan 28.

ATF6α promotes prostate cancer progression by enhancing PLA2G4A-mediated arachidonic acid metabolism and protecting tumor cells against ferroptosis.

Ru Zhao, Ye Lv, Tingting Feng, Ruojia Zhang, Luna Ge, Jihong Pan, Bo Han, Guanhua Song, Lin Wang.

  BACKGROUND: Despite the clinical success of androgen receptor (AR)-targeted therapies, prostate cancer (PCa) inevitably progresses to castration-resistant prostate cancer (CRPC). Transcription factor 6 α (ATF6α), an effector of the unfolded protein response (UPR) that modulates the cellular response to endoplasmic reticulum (ER) stress, has been linked to tumor development, metastasis, and relapse. However, the role of ATF6α in CRPC remains unclear.METHODS: The effect of ATF6α on the CRPC-like phenotype in PCa cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carb-Oxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS), 5-Bromo-2-deoxyUridine (BrdU) incorporation analysis, and cell death assay. Mechanistically, bioinformatic analysis was utilized to evaluate the potential of PLA2G4A as the target of ATF6α. Moreover, Western blot analysis, real-time polymerase chain reaction, chromatin immunoprecipitation, arachidonic acid (AA), and prostaglandin E2 (PGE2) assays were performed to identify the regulatory effect of ATF6α on PLA2G4A.
RESULTS: In this study, we found that the increase of ATF6α expression in response to androgen deprivation generates PCa cells with a CRPC-like phenotype. PCa cells with high levels of ATF6α expression are resistant to ferroptosis, and genetic and pharmacological inhibition of ATF6α could, therefore, promote the ferroptotic death of tumor cells and delay PCa progression. Molecular analyses linked ATF6α regulation of ferroptosis to the PLA2G4A-mediated release of AA and the resulting increase in PGE2 production, the latter of which acts as an antiferroptotic factor.
CONCLUSIONS: This study defines ATF6α as a novel antiferroptotic regulator that exacerbates PCa progression. In addition, our data establish ATF6α-PLA2G4A signaling as an important pathological pathway in PCa, and targeting this pathway may be a novel treatment strategy.

Keywords:  AA; ATF6α; CRPC; PGE2; PLA2G4A; ferroptosis

DOI:  https://doi.org/10.1002/pros.24308
Plant Cell. 2022 Jan 25. pii: koac017. [Epub ahead of print]

Reductive stress triggers ANAC017-mediated retrograde signaling to safeguard the endoplasmic reticulum by boosting mitochondrial respiratory capacity.

Philippe Fuchs, Finja Bohle, Sophie Lichtenauer, José Manuel Ugalde, Elias Feitosa Araujo, Berivan Mansuroglu, Cristina Ruberti, Stephan Wagner, Stefanie J Müller-Schüssele, Andreas J Meyer, Markus Schwarzländer.

Redox processes are at the heart of universal life processes, such as metabolism, signaling or folding of secreted proteins. Redox landscapes differ between cell compartments and are strictly controlled to tolerate changing conditions and to avoid cell dysfunction. While a sophisticated antioxidant network counteracts oxidative stress, our understanding of reductive stress responses remains fragmentary. Here, we observed root growth impairment in Arabidopsis thaliana mutants of mitochondrial alternative oxidase 1a (aox1a) in response to the model thiol reductant dithiothreitol (DTT). Mutants of mitochondrial uncoupling protein 1 (ucp1) displayed a similar phenotype indicating that impaired respiratory flexibility led to hypersensitivity. Endoplasmic reticulum (ER) stress was enhanced in the mitochondrial mutants and limiting endoplasmic reticulum oxidoreductin (ERO) capacity in the aox1a background led to synergistic root growth impairment by DTT, indicating that mitochondrial respiration alleviates reductive ER stress. The observations that DTT triggered NAD reduction in vivo and that the presence of thiols led to electron transport chain activity in isolated mitochondria offer a biochemical framework of mitochondrion-mediated alleviation of thiol-mediated reductive stress. Ablation of transcription factor ANAC017 impaired the induction of AOX1a expression by DTT and led to DTT hypersensitivity, revealing that reductive stress tolerance is achieved by adjusting mitochondrial respiratory capacity via retrograde signaling. Our data reveal an unexpected role for mitochondrial respiratory flexibility and retrograde signaling in reductive stress tolerance involving inter-organelle redox crosstalk.

DOI: https://doi.org/10.1093/plcell/koac017