Persulfidation of ATG18a regulates autophagy under ER stress in Arabidopsis

Hydrogen sulfide (H2S) is an endogenously generated gaseous signaling molecule, which recently has been implicated in autophagy regulation in both plants and mammals through persulfidation of specific targets. Persulfidation has been suggested as the molecular mechanism through which sulfide regulates autophagy in plant cells. ATG18a is a core autophagy component that is required for bulk autophagy and also for reticulophagy during endoplasmic reticulum (ER) stress. In this research, we revealed the role of sulfide in plant ER stress responses as a negative regulator of autophagy. We demonstrate that sulfide regulates ATG18a phospholipid-binding activity by reversible persulfidation at Cys103, and that this modification activates ATG18a binding capacity to specific phospholipids in a reversible manner. Our findings strongly suggest that persulfidation of ATG18a at C103 regulates autophagy under ER stress, and that the impairment of persulfidation affects both the number and size of autophagosomes.

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Role of Hydrogen Sulfide and 3-Mercaptopyruvate Sulfurtransferase in the Regulation of the Endoplasmic Reticulum Stress Response in Hepatocytes

Biomolecules ◽

10.3390/biom10121692 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1692

Author(s):

Theodora Panagaki ◽

Elisa B. Randi ◽

Csaba Szabo

Keyword(s):

Endoplasmic Reticulum ◽

Hydrogen Sulfide ◽

Liver Disease ◽

Er Stress ◽

Chronic Liver Disease ◽

Chronic Liver ◽

Endoplasmic Reticulum Stress Response ◽

Functional Responses ◽

Mercaptopyruvate Sulfurtransferase

It is estimated that over 1.5 billion people suffer from various forms of chronic liver disease worldwide. The emerging prevalence of metabolic syndromes and alcohol misuse, along with the lack of disease-modifying agents for the therapy of many severe liver conditions predicts that chronic liver disease will continue to be a major problem in the future. Better understanding of the underlying pathogenetic mechanisms and identification of potential therapeutic targets remains a priority. Herein, we explored the potential role of the 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide (H2S) system in the regulation of the endoplasmic reticulum (ER) stress and of its downstream processes in the immortalized hepatic cell line HepG2 in vitro. ER stress suppressed endogenous H2S levels and pharmacological supplementation of H2S with sodium hydrogen sulfide (NaHS) mitigated many aspects of ER stress, culminating in improved cellular bioenergetics and prevention of autophagic arrest, thereby switching cells’ fate towards survival. Genetic silencing of 3-MST or pharmacological inhibition of the key enzymes involved in hepatocyte H2S biosynthesis exacerbated many readouts related to ER-stress or its downstream functional responses. Our findings implicate the 3-MST/H2S system in the intracellular network that governs proteostasis and ER-stress adaptability in hepatocytes and reinforce the therapeutic potential of pharmacological H2S supplementation.

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Salicylic acid-independent role of NPR1 is required for protection from proteotoxic stress in the plant endoplasmic reticulum

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1802254115 ◽

2018 ◽

Vol 115 (22) ◽

pp. E5203-E5212 ◽

Cited By ~ 19

Author(s):

Ya-Shiuan Lai ◽

Luciana Renna ◽

John Yarema ◽

Cristina Ruberti ◽

Sheng Yang He ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Salicylic Acid ◽

Er Stress ◽

Stress Responses ◽

Unfolded Protein ◽

Redox Activation ◽

Genetic Level ◽

The Unfolded Protein Response ◽

Protein Response

The unfolded protein response (UPR) is an ancient signaling pathway designed to protect cells from the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER). Because misregulation of the UPR is potentially lethal, a stringent surveillance signaling system must be in place to modulate the UPR. The major signaling arms of the plant UPR have been discovered and rely on the transcriptional activity of the transcription factors bZIP60 and bZIP28 and on the kinase and ribonuclease activity of IRE1, which splices mRNA to activate bZIP60. Both bZIP28 and bZIP60 modulate UPR gene expression to overcome ER stress. In this study, we demonstrate at a genetic level that the transcriptional role of bZIP28 and bZIP60 in ER-stress responses is antagonized by nonexpressor of PR1 genes 1 (NPR1), a critical redox-regulated master regulator of salicylic acid (SA)-dependent responses to pathogens, independently of its role in SA defense. We also establish that the function of NPR1 in the UPR is concomitant with ER stress-induced reduction of the cytosol and translocation of NPR1 to the nucleus where it interacts with bZIP28 and bZIP60. Our results support a cellular role for NPR1 as well as a model for plant UPR regulation whereby SA-independent ER stress-induced redox activation of NPR1 suppresses the transcriptional role of bZIP28 and bZIP60 in the UPR.

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Hydrogen sulfide protects SH-SY5Y cells against 6-hydroxydopamine-induced endoplasmic reticulum stress

AJP Cell Physiology ◽

10.1152/ajpcell.00281.2011 ◽

2012 ◽

Vol 303 (1) ◽

pp. C81-C91 ◽

Cited By ~ 38

Author(s):

Li Xie ◽

Chi Xin Tiong ◽

Jin-Song Bian

Keyword(s):

Endoplasmic Reticulum ◽

Hydrogen Sulfide ◽

Protective Effect ◽

Er Stress ◽

Stress Responses ◽

Initiation Factor ◽

Akt Inhibitor ◽

Stress Injury ◽

Sodium Hydrosulfide ◽

6 Hydroxydopamine

Endoplasmic reticulum (ER) stress has been implicated in several neurodegenerative diseases, including Parkinson's disease. The present study attempted to investigate the effect of hydrogen sulfide (H2S) on 6-hydroxydopamine (6-OHDA)-induced ER stress in SH-SY5Y cells. We found in the present study that exogenous application of sodium hydrosulfide (NaHS; an H2S donor, 100 μM) significantly attenuated 6-OHDA (50 μM)-induced cell death. NaHS also reversed the upregulation of cleaved poly(ADP-ribose) polymerase and caspase 9 in 6-OHDA-treated cells. Consistent with its cytoprotective effects, NaHS markedly reduced 6-OHDA induced-ER stress responses, including the upregulated levels of eukaryotic initiation factor-2α phosphorylation, glucose-regulated protein 78, and C/EBP homologous protein expression. The protective effect of H2S on ER stress was attenuated by blockade of Akt activity with an Akt inhibitor or inhibition of heat shock protein (Hsp)90 with geldanamycin but not by suppression of ERK1/2 with PD-98059. Blockade of Akt also significantly decreased the protein abundance of Hsp90 in SH-SY5Y cells. Moreover, overexpression of cystathionine β-synthase (a main H2S-synthesizing enzyme in the brain) elevated the Hsp90 protein level and suppressed 6-OHDA-induced ER stress. In conclusion, the protective effect of H2S against 6-OHDA-induced ER stress injury in SH-SY5Y cells involves the Akt-Hsp90 pathway.

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Crosstalk between endoplasmic reticulum stress and oxidative stress: a dynamic duo in multiple myeloma

Cellular and Molecular Life Sciences ◽

10.1007/s00018-021-03756-3 ◽

2021 ◽

Author(s):

Sinan Xiong ◽

Wee-Joo Chng ◽

Jianbiao Zhou

Keyword(s):

Oxidative Stress ◽

Multiple Myeloma ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Cell Fate ◽

Stress Responses ◽

Plasma Cells ◽

Reactive Oxygen Species Generation ◽

Future Research ◽

And Oxidative Stress

AbstractUnder physiological and pathological conditions, cells activate the unfolded protein response (UPR) to deal with the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum. Multiple myeloma (MM) is a hematological malignancy arising from immunoglobulin-secreting plasma cells. MM cells are subject to continual ER stress and highly dependent on the UPR signaling activation due to overproduction of paraproteins. Mounting evidence suggests the close linkage between ER stress and oxidative stress, demonstrated by overlapping signaling pathways and inter-organelle communication pivotal to cell fate decision. Imbalance of intracellular homeostasis can lead to deranged control of cellular functions and engage apoptosis due to mutual activation between ER stress and reactive oxygen species generation through a self-perpetuating cycle. Here, we present accumulating evidence showing the interactive roles of redox homeostasis and proteostasis in MM pathogenesis and drug resistance, which would be helpful in elucidating the still underdefined molecular pathways linking ER stress and oxidative stress in MM. Lastly, we highlight future research directions in the development of anti-myeloma therapy, focusing particularly on targeting redox signaling and ER stress responses.

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c-Jun Inhibits Thapsigargin-Induced ER Stress Through Up-Regulation of DSCR1/Adapt78

Experimental Biology and Medicine ◽

10.3181/0803-rm-84 ◽

2008 ◽

Vol 233 (10) ◽

pp. 1289-1300 ◽

Cited By ~ 25

Author(s):

Peng Zhao ◽

Xiaoyan Xiao ◽

Agnes S. Kim ◽

M. Fatima Leite ◽

Jinxia Xu ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Wild Type Mouse ◽

Mouse Fibroblast ◽

Expression Levels ◽

Mouse Fibroblasts ◽

The Unfolded Protein Response ◽

Calcineurin Activity

The endoplasmic reticulum (ER) is exquisitely sensitive to changes in its internal environment. Various conditions, collectively termed “ER stress”, can perturb ER function, leading to the activation of a complex response known as the unfolded protein response (UPR). Although c-Jun N-terminal kinase (JNK) activation is nearly always associated with cell death by various stimuli, the functional role of JNK in ER stress-induced cell death remains unclear. JNK regulates gene expression through the phosphorylation and activation of transcription factors, such as c-Jun. Here, we investigated the role of c-Jun in the regulation of ER stress-related genes. c-Jun expression levels determined the response of mouse fibroblasts to ER stress induced by thapsigargin (TG, an inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase). c-jun−/− mouse fibroblast cells were more sensitive to TG-induced cell death compared to wild-type mouse fibroblasts, while reconstitution of c-Jun expression in c-jun−/− cells (c-Jun Re) enhanced resistance to TG-induced cell death. The expression levels of ER chaperones Grp78 and Gadd153 induced by TG were lower in c-Jun Re than in c-jun−/− cells. Moreover, TG treatment significantly increased calcineurin activity in c-jun−/− cells, but not in c-Jun Re cells. In c-Jun Re cells, TG induced the expression of Adapt78, also known as the Down syndrome critical region 1 (DSCR1), which is known to block calcineurin activity. Taken together, our findings suggest that c-Jun, a transcription factor downstream of the JNK signaling pathway, up-regulates Adapt78 expression in response to TG-induced ER stress and contributes to protection against TG-induced cell death.

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RHBDL4 protects against endoplasmic reticulum stress by regulating the morphology and distribution of ER sheets

10.1101/2021.06.15.448480 ◽

2021 ◽

Author(s):

Viorica Liebe Lastun ◽

Matthew Freeman

Keyword(s):

Cell Cycle ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Er Stress ◽

Liver Steatosis ◽

Physiological Role ◽

Cell Types ◽

Rhomboid Protease ◽

Rapid Changes

In metazoans, the architecture of the endoplasmic reticulum (ER) differs between cell types, and undergoes major changes through the cell cycle and according to physiological needs. Although much is known about how the different ER morphologies are generated and maintained, especially the ER tubules, how context dependent changes in ER shape and distribution are regulated and the factors involved are less characterized. Here, we show that RHBDL4, an ER-resident rhomboid protease, modulates the shape and distribution of the ER, especially under conditions that require rapid changes in the ER sheet distribution, including ER stress. RHBDL4 interacts with CLIMP-63, a protein involved in ER sheet stabilisation, and with the cytoskeleton. Mice lacking RHBDL4 are sensitive to ER stress and develop liver steatosis, a phenotype associated with unresolved ER stress. Our data introduce a new physiological role of RHBDL4 and also imply that this function does not require its enzymatic activity.

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Hydrogen sulfide alleviates hyperhomocysteinemia-mediated skeletal muscle atrophy via mitigation of oxidative and endoplasmic reticulum stress injury

AJP Cell Physiology ◽

10.1152/ajpcell.00147.2018 ◽

2018 ◽

Vol 315 (5) ◽

pp. C609-C622 ◽

Cited By ~ 17

Author(s):

Avisek Majumder ◽

Mahavir Singh ◽

Jyotirmaya Behera ◽

Nicholas T. Theilen ◽

Akash K. George ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Endoplasmic Reticulum ◽

Hydrogen Sulfide ◽

Er Stress ◽

Muscle Atrophy ◽

C2c12 Cells ◽

Skeletal Muscle Atrophy ◽

Stress Injury ◽

Western Blots

Although hyperhomocysteinemia (HHcy) occurs because of the deficiency in cystathionine-β-synthase (CBS) causing skeletal muscle dysfunction, it is still unclear whether this effect is mediated through oxidative stress, endoplasmic reticulum (ER) stress, or both. Nevertheless, there is no treatment option available to improve HHcy-mediated muscle injury. Hydrogen sulfide (H2S) is an antioxidant compound, and patients with CBS mutation do not produce H2S. In this study, we hypothesized that H2S mitigates HHcy-induced redox imbalance/ER stress during skeletal muscle atrophy via JNK phosphorylation. We used CBS+/−mice to study HHcy-mediated muscle atrophy, and treated them with sodium hydrogen sulfide (NaHS; an H2S donor). Proteins and mRNAs were examined by Western blots and quantitative PCR. Proinflammatory cytokines were also measured. Muscle mass and strength were studied via fatigue susceptibility test. Our data revealed that HHcy was detrimental to skeletal mass, particularly gastrocnemius and quadriceps muscle weight. We noticed that oxidative stress was reversed by NaHS in homocysteine (Hcy)-treated C2C12 cells. Interestingly, ER stress markers (GRP78, ATF6, pIRE1α, and pJNK) were elevated in vivo and in vitro, and NaHS mitigated these effects. Additionally, we observed that JNK phosphorylation was upregulated in C2C12 after Hcy treatment, but NaHS could not reduce this effect. Furthermore, inflammatory cytokines IL-6 and TNF-α were higher in plasma from CBS as compared with wild-type mice. FOXO1-mediated Atrogin-1 and MuRF-1 upregulation were attenuated by NaHS. Functional studies revealed that NaHS administration improved muscle fatigability in CBS+/−mice. In conclusion, our work provides evidence that NaHS is beneficial in mitigating HHcy-mediated skeletal injury incited by oxidative/ER stress responses.

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Abstract 357: Hepatic ERK2 Suppresses Endoplasmic Reticulum Stress, Leading to Protection from Oxidative Stress and Endothelial Dysfunction

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a357 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Takehiko Kujiraoka ◽

Yasushi Satoh ◽

Makoto Ayaori ◽

Yasunaga Shiraishi ◽

Yuko Arai-Nakaya ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Fatty Acid ◽

Endothelial Dysfunction ◽

Er Stress ◽

Vascular Complications ◽

Metabolic Remodeling ◽

And Oxidative Stress

Background Insulin signaling comprises 2 major cascades, the IRS/PI3K/Akt and Ras/Raf/MEK/ERK pathways. Many studies on the tissue-specific effects of the former pathway had been conducted, however, the role of the latter cascade in tissue-specific insulin resistance had not been investigated. High glucose/fatty acid toxicity, inflammation and oxidative stress, all of which are associated with insulin resistance, can activate ERK. Liver plays a central role of metabolism and hepatosteatosis (HST) is associated with vascular diseases. The aim of this study is to elucidate the role of hepatic ERK2 in HST, metabolic remodeling and endothelial dysfunction. Methods Serum biomarkers of vascular complications in human were compared between subjects with and without HST diagnosed by echography for regular medical checkup. Next, we created liver-specific ERK2 knockout mice (LE2KO) and fed them with a high-fat/high-sucrose diet (HFHSD) for 20 weeks. The histological analysis, the expression of hepatic sarco/endoplasmic reticulum (ER) Ca 2+ -ATPase 2 (SERCA2) and glucose-tolerance/insulin-sensitivity (GT/IS) were tested. Vascular superoxide production and endothelial function were evaluated with dihydroethidium staining and isometric tension measurement of aorta. Results The presence of HST significantly increased HOMA-IR, an indicator of insulin resistance or atherosclerotic index in human. HFHSD-fed LE2KO revealed a marked exacerbation in HST and metabolic remodeling represented by the impairment of GT/IS, elevated serum free fatty acid and hyperhomocysteinemia without changes in body weight, blood pressure and serum cholesterol/triglyceride levels. In the HFHSD-fed LE2KO, mRNA and protein expressions of hepatic SERCA2 were significantly decreased, which resulted in hepatic ER stress. Induction of vascular superoxide production and remarkable endothelial dysfunction were also observed in them. Conclusions Hepatic ERK2 revealed the suppression of hepatic ER stress and HST in vivo , which resulted in protection from vascular oxidative stress and endothelial dysfunction. HST with hepatic ER stress can be a prominent risk of vascular complications by metabolic remodeling and oxidative stress in obese-related diseases.

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Role of O-GlcNAcylation and endoplasmic reticulum stress on obesity and insulin resistance

Turkish Journal of Biochemistry ◽

10.1515/tjb-2018-0303 ◽

2019 ◽

Vol 44 (5) ◽

pp. 599-610 ◽

Cited By ~ 1

Author(s):

Benan Pelin Sermikli ◽

Gulizar Aydogdu ◽

Afsar Abbasi Taghidizaj ◽

Erkan Yilmaz

Keyword(s):

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Western Blot ◽

Er Stress ◽

Insulin Receptor ◽

Serine Phosphorylation ◽

Wild Type ◽

Adipose Tissues ◽

Insulin Resistant

Abstract Background Obesity is a global public health problem. Obesity closely associated with various metabolic diseases such as; insulin resistance, hypertension, dyslipidemia and cardiovascular diseases. Endoplasmic reticulum (ER) stress is a critical factor for insulin resistance. O-linked N-acetyl-glucosamine (O-GlcNAc); is the post-translational modification which is has a vital role in biological processes; including cell signaling, in response to nutrients, stress and other extracellular stimuli. Materials and methods In this study, we aimed to investigate the role of O-GlcNAc modification in the context of obesity and obesity-associated insulin resistance in adipose tissue. For this purpose, first, the visceral and epididymal adipose tissues of obese and insulin resistant C57BL/6 Lepob/Lepob and wild-type mice were used to determine the O-GlcNAc modification pattern by western blot. Secondly, the external stimulation of O-GlcNAc modification in wild-type mice achieved by intraperitoneal 5 mg/kg/day glucosamine injection every 24 h for 5 days. The effect of increased O-GlcNAc modification on insulin resistance and ER stress investigated in adipose tissues of glucosamine challenged wild-type mice through regulation of the insulin signaling pathway and unfolded protein response (UPR) elements by western blot. In addition to that, the O-GlcNAc status of the insulin receptor substrate-1 (IRS1) investigated in epididymal and visceral adipose tissues of ob/ob, wild-type and glucosamine challenged mice by immunoprecipitation. Results We found that reduced O-GlcNAc levels in visceral and epididymal adipose tissues of obese and insulin-resistant ob/ob mice, although interestingly we observed that increased O-GlcNAc modification in glucosamine challenged wild-type mice resulted in insulin resistance and ER stress. Furthermore, we demonstrated that the IRS1 was modified with O-GlcNAc in visceral and epididymal adipose tissues in both ob/ob mice and glucosamine-injected mice, and was compatible with the serine phosphorylation of this modification. Conclusion Our results suggest that O-GlcNAcylation of proteins is a crucial factor for intracellular trafficking regulates insulin receptor signaling and UPR depending on the cellular state of insulin resistance.

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Chemotherapy Resistance Explained through Endoplasmic Reticulum Stress-Dependent Signaling

Cancers ◽

10.3390/cancers11030338 ◽

2019 ◽

Vol 11 (3) ◽

pp. 338 ◽

Cited By ~ 17

Author(s):

Entaz Bahar ◽

Ji-Ye Kim ◽

Hyonok Yoon

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Molecular Mechanism ◽

Molecular Mechanisms ◽

Cellular Proliferation ◽

Protein Quality ◽

Chemotherapy Resistance ◽

Persistent Problem ◽

Stress Dependent ◽

The Relationship

Cancers cells have the ability to develop chemotherapy resistance, which is a persistent problem during cancer treatment. Chemotherapy resistance develops through different molecular mechanisms, which lead to modification of the cancer cells signals needed for cellular proliferation or for stimulating an immune response. The endoplasmic reticulum (ER) is an important organelle involved in protein quality control, by promoting the correct folding of protein and ER-mediated degradation of unfolded or misfolded protein, namely, ER-associated degradation. Disturbances of the normal ER functions causes an accumulation of unfolded or misfolded proteins in the ER lumen, resulting in a condition called “ER stress (ERS).” ERS triggers the unfolded protein response (UPR)—also called the ERS response (ERSR)—to restore homeostasis or activate cell death. Although the ERSR is one emerging potential target for chemotherapeutics to treat cancer, it is also critical for chemotherapeutics resistance, as well. However, the detailed molecular mechanism of the relationship between the ERSR and tumor survival or drug resistance remains to be fully understood. In this review, we aim to describe the most vital molecular mechanism of the relationship between the ERSR and chemotherapy resistance. Moreover, the review also discusses the molecular mechanism of ER stress-mediated apoptosis on cancer treatments.

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