bims-unfpre 2023-12-03 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2023–12–03
eight papers selected by
Susan Logue, University of Manitoba

Cutting through the stress: RNA decay pathways at the endoplasmic reticulum.
Strategies targeting endoplasmic reticulum stress to improve Parkinson's disease.
Inhibiting the endoplasmic reticulum stress response enhances the effect of doxorubicin by altering the lipid metabolism of liver cancer cells.
Cardioprotective anti-hyperglycemic drugs ameliorate endoplasmic reticulum (ER) stress.
MOS4-associated complex contributes to proper splicing and suppression of ER stress under long-term heat stress in Arabidopsis.
Olfaction: an emerging regulator of longevity and metabolism.
Synergistic lethality in chronic myeloid leukemia - targeting oxidative phosphorylation and unfolded protein response effectively complements tyrosine kinase inhibitor treatment.
Predicting the prognosis in patients with sepsis by an endoplasmic reticulum stress gene signature.

Trends Cell Biol. 2023 Nov 25. pii: S0962-8924(23)00236-2. [Epub ahead of print]

Cutting through the stress: RNA decay pathways at the endoplasmic reticulum.

Franziska Ottens, Sotirios Efstathiou, Thorsten Hoppe.

  The endoplasmic reticulum (ER) is central to the processing of luminal, transmembrane, and secretory proteins, and maintaining a functional ER is essential for organismal physiology and health. Increased protein-folding load on the ER causes ER stress, which activates quality control mechanisms to restore ER function and protein homeostasis. Beyond protein quality control, mRNA decay pathways have emerged as potent ER fidelity regulators, but their mechanistic roles in ER quality control and their interrelationships remain incompletely understood. Herein, we review ER-associated RNA decay pathways - including regulated inositol-requiring enzyme 1α (IRE1α)-dependent mRNA decay (RIDD), nonsense-mediated mRNA decay (NMD), and Argonaute-dependent RNA silencing - in ER homeostasis, and highlight the intricate coordination of ER-targeted RNA and protein decay mechanisms and their association with antiviral defense.

Keywords:  AGO2; ER quality control; RNA degradation; UPR; proteostasis; ubiquitin

DOI:  https://doi.org/10.1016/j.tcb.2023.11.003
Front Pharmacol. 2023 ;14 1288894

Strategies targeting endoplasmic reticulum stress to improve Parkinson's disease.

Danni Wang, Shuhui Qu, Zaijun Zhang, Liang Tan, Xiuping Chen, Hai-Jing Zhong, Cheong-Meng Chong.

  Parkinson's disease (PD) is a common neurodegenerative disorder with motor symptoms, which is caused by the progressive death of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Accumulating evidence shows that endoplasmic reticulum (ER) stress occurring in the SNpc DA neurons is an early event in the development of PD. ER stress triggers the activation of unfolded protein response (UPR) to reduce stress and restore ER function. However, excessive and continuous ER stress and UPR exacerbate the risk of DA neuron death through crosstalk with other PD events. Thus, ER stress is considered a promising therapeutic target for the treatment of PD. Various strategies targeting ER stress through the modulation of UPR signaling, the increase of ER's protein folding ability, and the enhancement of protein degradation are developed to alleviate neuronal death in PD models. In this review, we summarize the pathological role of ER stress in PD and update the strategies targeting ER stress to improve ER protein homeostasis and PD-related events.

Keywords:  ER stress; Parkinson’s disease; dopaminergic neurons; protein homeostasis; unfolded protein response

DOI:  https://doi.org/10.3389/fphar.2023.1288894
Mol Metab. 2023 Nov 27. pii: S2212-8778(23)00180-1. [Epub ahead of print] 101846

Inhibiting the endoplasmic reticulum stress response enhances the effect of doxorubicin by altering the lipid metabolism of liver cancer cells.

Maria Kopsida, Ada Lerma Clavero, Jaafar Khaled, David Balgoma, Clara Luna-Marco, Azazul Chowdhury, Sofi Sennefelt Nyman, Fredrik Rorsman, Charlotte Ebeling Barbier, Peter Bergsten, Hans Lennernäs, Mikael Hedeland, Femke Heindryckx.

  Hepatocellular carcinoma (HCC) is characterized by a low and variable response to chemotherapeutic treatments. One contributing factor to the overall pharmacodynamics is the activation of endoplasmic reticulum (ER) stress pathways. This is a cellular stress mechanism that becomes activated when the cell´s need for protein synthesis surpasses the ER´s capacity to maintain accurate protein folding, and has been implicated in creating drug-resistance in several solid tumors.
OBJECTIVE: to identify the role of ER-stress and lipid metabolism in mediating drug response in HCC.
METHODS: By using a chemically-induced mouse model for HCC, we administered the ER-stress inhibitor 4μ8C and/or DOX twice weekly for three weeks post-tumor initiation. Histological analyses were performed alongside comprehensive molecular biology and lipidomics assessments of isolated liver samples. In vitro models, including HCC cells, spheroids, and patient-derived liver organoids were subjected to 4μ8C and/or DOX, enabling us to assess their synergistic effects on cellular viability, lipid metabolism, and oxygen consumption rate.
RESULTS: we reveal a pivotal synergy between ER-stress modulation and drug response in HCC. The inhibition of ER-stress using 4μ8C not only enhances the cytotoxic effect of DOX, but also significantly reduces cellular lipid metabolism. This intricate interplay culminates in the deprivation of energy reserves essential for the sustenance of tumor cells.
CONCLUSIONS: This study elucidates the interplay between lipid metabolism and ER-stress modulation in enhancing doxorubicin efficacy in HCC. This novel approach not only deepens our understanding of the disease, but also uncovers a promising avenue for therapeutic innovation. The long-term impact of our study could open the possibility of ER-stress inhibitors and/or lipase inhibitors as adjuvant treatments for HCC-patients.

Keywords:  Lipidomics; chemotherapy; endoplasmic reticulum stress; hepatocellular carcinoma

DOI:  https://doi.org/10.1016/j.molmet.2023.101846
Am J Physiol Cell Physiol. 2023 Nov 27.

Cardioprotective anti-hyperglycemic drugs ameliorate endoplasmic reticulum (ER) stress.

Arshag D Mooradian, Michael J Haas.

  Cellular stress, notably oxidative, inflammatory and endoplasmic reticulum (ER) stress is implicated in the pathogenesis of cardiovascular disease. Modifiable risk factors for cardiovascular disease such as diabetes, hypercholesterolemia, saturated fat consumption, hypertension and cigarette smoking cause ER stress while currently known cardioprotective drugs with diverse pharmacodynamics share a common pleiotropic effect of reducing ER stress. Selective targeting of oxidative stress with known antioxidative vitamins has been ineffective in reducing cardiovascular risk. This "antioxidant paradox" is partially attributed to the unexpected aggravation of ER stress by the antioxidative agents used. In contrast, some of the contemporary anti-hyperglycemic drugs inhibit both oxidative stress and ER stress in human coronary artery endothelial cells. Unlike sulfonylureas, meglitinides, α glucosidase inhibitors and thiazolidinediones, metformin, glucagon like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors are the only anti-hyperglycemic drugs that reduce ER stress caused by pharmacological agents (tunicamycin) or hyperglycemic conditions. Clinical trials with selective ER stress modifiers are needed to test the suitability of ER stress as a therapeutic target for cardiovascular disease.

Keywords:  Anti-hyperglycemic; Cardioprotection; Endoplasmic reticulum stress; Glucagon like peptide one receptor agonists;; Sodium glucose cotransporter two inhibitors

DOI:  https://doi.org/10.1152/ajpcell.00470.2023
PNAS Nexus. 2023 Nov;2(11): pgad329

MOS4-associated complex contributes to proper splicing and suppression of ER stress under long-term heat stress in Arabidopsis.

Naoya Endo, Ryo Tsukimoto, Kazuho Isono, Akito Hosoi, Ryo Yamaguchi, Keisuke Tanaka, Satoshi Iuchi, Izumi Yotsui, Yoichi Sakata, Teruaki Taji.

  Plants are often exposed not only to short-term (S-) but also to long-term (L-)heat stress over several consecutive days. A few Arabidopsis mutants defective in L-heat tolerance have been identified, but the molecular mechanisms are less understood for this tolerance than for S-heat stress tolerance. To elucidate the mechanisms of the former, we used a forward genetic screen for sensitive to long-term heat (sloh) mutants and isolated sloh3 and sloh63. The mutants were hypersensitive to L- but not to S-heat stress, and sloh63 was also hypersensitive to salt stress. We identified the causal genes, SLOH3 and SLOH63, both of which encoded splicing-related components of the MOS4-associated complex (MAC). This complex is widely conserved in eukaryotes and has been suggested to interact with spliceosomes. Both genes were induced by L-heat stress in a time-dependent manner, and some abnormal splicing events were observed in both mutants under L-heat stress. In addition, endoplasmic reticulum (ER) stress and subsequent unfolded protein response occurred in both mutants under L-heat stress and were especially prominent in sloh63, suggesting that enhanced ER stress is due to the salt hypersensitivity of sloh63. Splicing inhibitor pladienolide B led to concentration-dependent disturbance of splicing, decreased L-heat tolerance, and enhanced ER stress. These findings suggest that maintenance of precise mRNA splicing under L-heat stress by the MAC is important for L-heat tolerance and suppressing ER stress in Arabidopsis.

Keywords:  Arabidopsis; ER stress; heat tolerance; long-term heat stress; selective splicing

DOI:  https://doi.org/10.1093/pnasnexus/pgad329
Trends Cell Biol. 2023 Nov 25. pii: S0962-8924(23)00234-9. [Epub ahead of print]

Olfaction: an emerging regulator of longevity and metabolism.

Maximillian A Thompson, Evandro A De-Souza.

  Ageing is a malleable process influenced by the environment. Recent research reveals that neurons interact with peripheral organs to regulate metabolism and longevity by responding to olfactory cues through specific pathways, such as the unfolded protein response (UPR) and microRNAs. Here, we examine the significance of these findings.

Keywords:  environmental cues; longevity; odorants; proteostasis; stress responses

DOI:  https://doi.org/10.1016/j.tcb.2023.11.001
BMC Cancer. 2023 Nov 27. 23(1): 1153

Synergistic lethality in chronic myeloid leukemia - targeting oxidative phosphorylation and unfolded protein response effectively complements tyrosine kinase inhibitor treatment.

Lukas Häselbarth, Sara Gamali, Domenica Saul, Manuela Krumbholz, Romy Böttcher-Loschinski, Martin Böttcher, Deyu Zou, Markus Metzler, Axel Karow, Dimitrios Mougiakakos.

  Chronic myeloid leukemia (CML) is effectively treated with tyrosine kinase inhibitors (TKIs), targeting the BCR::ABL1 oncoprotein. Still, resistance to therapy, relapse after treatment discontinuation, and side effects remain significant issues of long-term TKI treatment. Preliminary studies have shown that targeting oxidative phosphorylation (oxPhos) and the unfolded protein response (UPR) are promising therapeutic approaches to complement CML treatment. Here, we tested the efficacy of different TKIs, combined with the ATP synthase inhibitor oligomycin and the ER stress inducer thapsigargin in the CML cell lines K562, BV173, and KU812 and found a significant increase in cell death. Both, oligomycin and thapsigargin, triggered the upregulation of the UPR proteins ATF4 and CHOP, which was inhibited by imatinib. We observed comparable effects on cell death when combining TKIs with the ATP synthase inhibitor 8-chloroadenosine (8-Cl-Ado) as a potentially clinically applicable therapeutic agent. Stress-related apoptosis was triggered via a caspase cascade including the cleavage of caspase 3 and the inactivation of poly ADP ribose polymerase 1 (PARP1). The inhibition of PARP by olaparib also increased CML death in combination with TKIs. Our findings suggest a rationale for combining TKIs with 8-Cl-Ado or olaparib for future clinical studies in CML.

Keywords:  8-chloroadenosine; ATF4; CML; Caspase 3; Olaparib; Oligomycin; Oxidative phosphorylation; PARP; TKI; Thapsigargin; UPR

DOI:  https://doi.org/10.1186/s12885-023-11623-6
Aging (Albany NY). 2023 Nov 25. 15

Predicting the prognosis in patients with sepsis by an endoplasmic reticulum stress gene signature.

Jian Liu, Hao Wang, Huimin Xiao, Li Ji, Yonghui Yao, Chunshui Cao, Yong Liu, Liang Huang.

   BACKGROUND: Prognostic stratification of patients with sepsis is important for the development of individualized treatment strategies. Endoplasmic reticulum stress (ERS) plays a key role in sepsis. This study aimed to identify a set of genes related to ER stress to construct a predictive model for the prognosis of sepsis.
METHODS: The transcriptomic and clinical data of 479 sepsis patients were obtained from GSE65682 and divided into a training set (n=288) and a validation set (n=191) at a ratio of 3:2. The external test set was GSE95233 (n=51). LASSO and Cox regression analyses were performed to establish a signature to predict the prognosis of patients with sepsis. Moreover, we developed a nomogram that included the risk signature and clinical features to predict survival probability.
RESULTS: A prognostic signature was constructed with ten endoplasmic reticulum related genes (ADRB2, DHCR7, GABARAPL2, MAOA, MPO, PDZD8, QDPR, SCAP, TFRC, and TLR4) in the training set, which significantly divided patients with sepsis into high- and low-risk groups in terms of survival. This signature was validated using validation and external test sets. A nomogram based on the risk signature was constructed to quantitatively predict the prognosis of patients with sepsis.
CONCLUSIONS: We constructed an ERS signature as a novel prognostic marker for predicting survival in sepsis patients, which could be used to develop novel biomarkers for the diagnosis, treatment, and prognosis of sepsis and to provide new ideas and prospects for future clinical research.

Keywords:  biomarkers; endoplasmic reticulum stress; prognosis; sepsis; signature

DOI:  https://doi.org/10.18632/aging.205252