bims-unfpre 2024-09-29 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2024–09–29
eight papers selected by
Susan Logue, University of Manitoba

ER stress modulates Kv1.5 channels via PERK branch in HL-1 atrial myocytes: Relevance to atrial arrhythmogenesis and the effect of tetramethylpyrazine.
Cadmium toxicity on endoplasmic reticulum functioning.
Mechanisms of ferroptosis and the relationship between ferroptosis and ER stress after JEV and HSV infection.
Modulating the unfolded protein response with ISRIB mitigates cisplatin ototoxicity.
SIK2 Controls the Homeostatic Character of the POMC Secretome Acutely in Response to Pharmacological ER Stress Induction.
ER Stress and Mitochondrial Perturbations Regulate Cell Death in Retinal Detachment: Exploring the Role of HIF1α.
Temperature-dependent lifespan extension is achieved in miR-80-deleted Caenorhabditis elegans by NLP-45 to modulate endoplasmic reticulum unfolded protein responses.
Endoplasmic reticulum stress response pathway-mediated cell death in ovarian cancer.

Heliyon. 2024 Sep 30. 10(18): e37767

ER stress modulates Kv1.5 channels via PERK branch in HL-1 atrial myocytes: Relevance to atrial arrhythmogenesis and the effect of tetramethylpyrazine.

Xiang-Chong Wang, Yang Zhou, Huan-Xin Chen, Hai-Tao Hou, Guo-Wei He, Qin Yang.

  Endoplasmic reticulum (ER) stress is implicated in cardiac arrhythmia whereas the associated mechanisms remain inadequately understood. Kv1.5 channels are essential for atrial repolarization. Whether ER stress affects Kv1.5 channels is unknown. This study aimed to elucidate the response of Kv1.5 channels to ER stress by clarifying the unfolded protein response (UPR) branch responsible for the channel modulation. In addition, the effect of tetramethylpyrazine (TMP) on Kv1.5 channels was studied. Patch clamp and western-blot results revealed that exposure of HL-1 atrial myocytes to ER stress inducer tunicamycin upregulates Kv1.5 expression, increases Kv1.5 channel current (I Kur ) (14.91 ± 1.11 vs. 6.11 ± 1.31 pA/pF, P < 0.001), and shortened action potential duration (APD) (APD90: 82.79 ± 5.25 vs.121.11 ± 6.72 ms, P < 0.01), which could be reverted by ER stress inhibitors. Blockade of the PERK branch while not IRE1 and ATF6 branches of UPR downregulated Kv1.5 expression, accompanied by a decreased I Kur (9.03 ± 0.99 pA/pF) and a prolonged APD90 (113.69 ± 4.41 ms) (P < 0.01). PERK-mediated increases of Kv1.5 expression and I Kur were also observed in HL-1 cells incubated with thapsigargin. TMP suppressed the enhancement of I Kur (10.52 ± 0.97 vs. 17.52 ± 2.25 pA/pF, P < 0.05), prevented the shortening of APD (APD90: 110.16 ± 5.36 vs. 84.84 ± 4.58 ms, P < 0.05), and inhibited the upregulation of Kv1.5 triggered by ER stress. Our study suggests that ER stress induces upregulation and activation of Kv1.5 channels in atrial myocytes through the PERK branch of UPR. TMP prevents Kv1.5 upregulation/activation and the resultant APD shortening by inhibiting ER stress. These results may shed light on the mechanisms of atrial arrhythmogenesis and the antiarrhythmic effect of the traditional Chinese herb TMP.

Keywords:  Action potential duration; Arrhythmogenesis; Endoplasmic reticulum stress; Traditional Chinese medicine

DOI:  https://doi.org/10.1016/j.heliyon.2024.e37767
Int J Biochem Mol Biol. 2024 ;15(4): 107-117

Cadmium toxicity on endoplasmic reticulum functioning.

Shivani Mishra, Ramakrushna Paul, Vibha Rani, Debasish Kumar Ghosh, Buddhi Prakash Jain.

  Cadmium (Cd) is a heavy metal pollutant widely distributed in the environment due to industrial activities, mining, and agricultural practices. Cadmium-induced Toxicity exerts profound effects on ER functioning through multiple mechanisms, leading to cellular dysfunction and pathological consequences. Cadmium disrupts protein folding and activates the unfolded protein response (UPR). Cd exposure leads to the accumulation of misfolded proteins, triggering UPR pathways mediated by critical ER transmembrane sensors: IRE1, PERK, and ATF6. The subsequent UPR aims to restore ER homeostasis but can also induce apoptosis under severe stress conditions. Cd disrupts ER calcium homeostasis by inhibiting the SERCA pump, further exacerbating ER stress. The generation of reactive oxygen species (ROS also plays a critical role in Cd toxicity, damaging ER-resident proteins and amplifying UPR activation). Cadmium also affects the lipid metabolism. This review examines the mechanisms by which Cd toxicity impairs ER functioning, disruption of protein folding and quality control mechanisms, and dysregulation of calcium signaling and lipid metabolism. The subsequent cellular consequences, including oxidative stress, apoptosis, and inflammation, are discussed in the context of Cd-induced pathogenesis of diseases such as Cancer and neurodegenerative and cardiovascular disorders. Finally, potential therapeutic strategies must be explored to mitigate the adverse effects of Cd on ER functioning and human health.

Keywords:  Heavy metal; cadmium; endoplasmic reticulum; lipid metabolism; unfolded protein response

DOI:  https://doi.org/10.62347/OUDS3732
Front Microbiol. 2024 ;15 1415417

Mechanisms of ferroptosis and the relationship between ferroptosis and ER stress after JEV and HSV infection.

Rui Zhou, Kexin Wei, Xinyu Li, Beibei Yan, Lin Li.

  Ferroptosis is a novel form of programmed cell death, which is different from apoptosis, pyroptosis and autophagy in morphology and biochemistry. Ferroptosis is characterized by condensed mitochondrial membrane densities, vanished of mitochondria crista and outer membrane rupture in morphology, and the accumulation of intracellular iron, lipid peroxidation (LPO), decrease of GSH and inhibition of GPX4 in biochemistry. Japanese encephalitis virus (JEV) and Herpes simplex virus (HSV) are both common neurotropic viruses that can cause neurological disorders, such as severe encephalitis. JEV and HSV have been demonstrated to be able to induce ferroptosis. This process is closely related to the inhibition of the GSH-GPX4 system, ACSL4 phosphorylation, and Nrf2 ubiquitination. In this review, we summarized the mechanisms by which JEV and HSV induced ferroptosis in the current study. In addition, we found a strong relationship between endoplasmic reticulum (ER) stress and ferroptosis, and we therefore speculated that sustained ER stress might be a prerequisite for ferroptosis in JEV and HSV-induced diseases.

Keywords:  ER stress; Ferroptosis; HSV; JEV; LPO; ROS

DOI:  https://doi.org/10.3389/fmicb.2024.1415417
Sci Rep. 2024 Sep 27. 14(1): 22382

Modulating the unfolded protein response with ISRIB mitigates cisplatin ototoxicity.

Jiang Li, Stephanie L Rouse, Ian R Matthews, Yesai Park, Yasmin Eltawil, Elliott H Sherr, Dylan K Chan.

  Cisplatin is a commonly used chemotherapy agent with a nearly universal side effect of sensorineural hearing loss. The cellular mechanisms underlying cisplatin ototoxicity are poorly understood. Efforts in drug development to prevent or reverse cisplatin ototoxicity have largely focused on pathways of oxidative stress and apoptosis. An effective treatment for cisplatin ototoxicity, sodium thiosulfate (STS), while beneficial when used in standard risk hepatoblastoma, is associated with reduced survival in disseminated pediatric malignancy, highlighting the need for more specific drugs without potential tumor protective effects. The unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways have been shown to be involved in the pathogenesis of noise-induced hearing loss and cochlear synaptopathy in vivo, and these pathways have been implicated broadly in cisplatin cytotoxicity. This study sought to determine whether the UPR can be targeted to prevent cisplatin ototoxicity. Neonatal cochlear cultures and HEK cells were exposed to cisplatin, and UPR marker gene expression and cell death measured. Treatment with ISRIB (Integrated Stress Response InhIBitor), a drug that activates eif2B and downregulates the pro-apoptotic PERK/CHOP pathway of the UPR, was tested for its ability to reduce apoptosis in HEK cells, hair-cell death in cochlear cultures, and hearing loss using an in vivo mouse model of cisplatin ototoxicity. Finally, to evaluate whether ISRIB might interfere with cisplatin chemoeffectiveness, we tested it in head and neck squamous cell carcinoma (HNSCC) cell-based assays of cisplatin cytotoxicity. Cisplatin exhibited a biphasic, non-linear dose-response of cell death and apoptosis that correlated with different patterns of UPR marker gene expression in HEK cells and cochlear cultures. ISRIB treatment protected against cisplatin-induced hearing loss and hair-cell death, but did not impact cisplatin's cytotoxic effects on HNSCC cell viability, unlike STS. These findings demonstrate that targeting the pro-apoptotic PERK/CHOP pathway with ISRIB can mitigate cisplatin ototoxicity without reducing anti-cancer cell effects, suggesting that this may be a viable strategy for drug development.

Keywords:  Cisplatin; Endoplasmic reticulum stress; Ototoxicity; Unfolded protein response

DOI:  https://doi.org/10.1038/s41598-024-70561-w
Cells. 2024 Sep 17. pii: 1565. [Epub ahead of print]13(18):

SIK2 Controls the Homeostatic Character of the POMC Secretome Acutely in Response to Pharmacological ER Stress Induction.

Mehmet Soner Türküner, Ayşe Yazıcı, Ferruh Özcan.

  The neuronal etiology of obesity is centered around a diet-induced inflammatory state in the arcuate nucleus of the hypothalamus, which impairs the functionality of pro-opiomelanocortine neurons (POMCs) responsible for whole-body energy homeostasis and feeding behavior. Intriguingly, systemic salt inducible kinase 2 (SIK2) knockout mice demonstrated reduced food intake and energy expenditure along with modestly dysregulated metabolic parameters, suggesting a causal link between the absence of SIK2 activity in POMCs and the observed phenotype. To test this hypothesis, we conducted a comparative secretomics study from POMC neurons following pharmacologically induced endoplasmic reticulum (ER) stress induction, a hallmark of metabolic inflammation and POMC dysregulation in diet-induced obese (DIO) mice. Our data provide significant in vitro evidence for the POMC-specific SIK2 activity in controlling energy metabolism and feeding in DIO mice by regulating the nature of the related POMC secretome. Our data also suggest that under physiological stress conditions, SIK2 may act as a gatekeeper for the secreted inflammatory factors and signaling molecules critical for cellular survival and energy homeostasis. On the other hand, in the absence of SIK2, the gate opens, leading to a surge of inflammatory cytokines and apoptotic cues concomitant with the dysregulation of POMC neurons.

Keywords:  ER stress; POMC; SIK2; hypothalamic obesity; inflammation; neuronal secretome

DOI:  https://doi.org/10.3390/cells13181565
Invest Ophthalmol Vis Sci. 2024 Sep 03. 65(11): 39

ER Stress and Mitochondrial Perturbations Regulate Cell Death in Retinal Detachment: Exploring the Role of HIF1α.

Bhavneet Kaur, Bruna Miglioranza Scavuzzi, Mengling Yang, Jingyu Yao, Lin Jia, Steven F Abcouwer, David N Zacks.

Purpose: Retinal detachment (RD) leads to photoreceptor (PR) hypoxia due to separation from the retinal pigment epithelium (RPE). Hypoxia stabilizes retinal hypoxia-inducible factor 1-alpha (HIF1α), crucial for PR survival during RD. This study explores the regulatory role of HIF1α in PR cell survival pathways during RD.
Methods: Experimental RD was created in C57BL/6J and HIF1αΔrod mice by injecting 1% hyaluronic acid into the subretinal space. The 661W photoreceptor cells were exposed to hypoxic conditions. Markers of endoplasmic reticulum stress (ERS), mitophagy, and accumulation of polyubiquinated proteins were evaluated using RT-PCR and western blot analyses. Cell death of PR cells was quantified using trypan blue exclusion assay and TUNEL staining. Retinal cell death was assessed using a DNA fragmentation assay.
Results: In C57BL/6J mice and 661W cells, there were increases in HIF1α protein levels: 2.2-fold after RD (P = 0.04) and threefold after hypoxia (P = 0.057). Both the in vivo and in vitro RD models showed increased protein expression of ERS markers (including BIP, CHOP, and IRE1α), mitophagy markers (Parkin, PINK, and FUNDC1), and polyubiquitinated proteins. In 661W cells, hypoxia resulted in a loss of mitochondrial membrane potential, an increase in mitochondrial reactive oxygen species, and a decrease in intracellular adenosine triphosphate levels. Lack of HIF1α in rods blocked the upregulation of mitophagy markers after RD.
Conclusions: RD results in the activation of ERS, mitophagy, mitochondrial dysfunction, and accumulation of polyubiquitinated proteins. Results suggest a role for HIF1α in activation of the mitophagy pathway after RD, which may serve to protect the PR cells.

DOI: https://doi.org/10.1167/iovs.65.11.39
Aging Cell. 2024 Sep 25. e14345

Temperature-dependent lifespan extension is achieved in miR-80-deleted Caenorhabditis elegans by NLP-45 to modulate endoplasmic reticulum unfolded protein responses.

Chunlin Zhao, Jintao Luo, Yuqiang Zhang, Yong Yu.

  MicroRNA plays a crucial role in post-transcriptional gene regulation and has recently emerged as a factor linked to aging, but the underlying regulatory mechanisms remain incompletely understood. In this study, we observed lifespan-extending effects in miR-80-deficient Caenorhabditis elegans at 20°C but not 25°C. At 20°C, miR-80 deletion leads to NLP-45 upregulation, which positively correlates to increased abu transcripts and extended lifespan. Supportively, we identified miR-80 binding regions in the 5' and 3' UTR of nlp-45. As the temperature rises to 25°C, wildtype increases miR-80 levels, but removal of miR-80 is accompanied by decreased nlp-45 expression, suggesting intervention from other temperature-sensitive mechanisms. These findings support the concept that microRNAs and neuropeptide-like proteins can form molecular regulatory networks involving downstream molecules to regulate lifespan, and such regulatory effects vary on environmental conditions. This study unveils the role of an axis of miR-80/NLP-45/UPRER components in regulating longevity, offering new insights on strategies of aging attenuation and health span prolongation.

Keywords:   Caenorhabditis elegans ; miR‐80 ; NLP‐45; aging; endoplasmic reticulum stress

DOI:  https://doi.org/10.1111/acel.14345
Front Oncol. 2024 ;14 1446552

Endoplasmic reticulum stress response pathway-mediated cell death in ovarian cancer.

Qiaochu Chen, Chan Li, Wei Wei, Jia Li, Fangyuan Liu, Yuqian Fu, Liping Tang, Fengjuan Han.

  The endoplasmic reticulum (ER) is one of the largest organelles, and Endoplasmic Reticulum Stress Response Pathway is a series of responses triggered by the homeostatic imbalance of the ER and the state in which unfolded or misfolded proteins accumulate in the ER, which can trigger cell death. Cell death plays a crucial role in the development of diseases such as gynecological oncology. Herein, we review the current research on the response and ovarian cancer, discussing the key sensors (IRE1, PERK, ATF6), and the conditions under which it occurs (Ca2+ homeostasis disruption, hypoxia, others). Using the response as a starting point, provide a comprehensive overview of the relationship with the four types of cell death (apoptosis, autophagy, immunogenic cell death, paraptosis) in an attempt to provide new targeted therapeutic strategies for the organelle-Endoplasmic Reticulum Stress Response Pathway-cell death in ovarian cancer therapy.

Keywords:  cell biology; cell death; endoplasmic reticulum stress response pathway; organelle; ovarian cancer; potential therapeutic strategies

DOI:  https://doi.org/10.3389/fonc.2024.1446552