bims-unfpre 2023-06-04 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2023–06–04
eight papers selected by
Susan Logue, University of Manitoba

The mechanisms to dispose of misfolded proteins in the endoplasmic reticulum of adipocytes.
Bone and the Unfolded Protein Response: In Sickness and in Health.
HMGB1-induced activation of ER stress contributes to pulmonary artery hypertension in vitro and in vivo.
Non-coding RNA mediates endoplasmic reticulum stress-induced apoptosis in heart disease.
A Native Drug-Free Macromolecular Therapeutic to Trigger Mutual Reinforcing of Endoplasmic Reticulum Stress and Mitochondrial Dysfunction for Cancer Treatment.
ATF6 is a critical regulator of cadmium-mediated apoptosis in spermatocytes.
Role of endoplasmic reticulum autophagy in acute lung injury.
Role of UPRmt and mitochondrial dynamics in host immunity: it takes two to tango.

Nat Commun. 2023 May 30. 14(1): 3132

The mechanisms to dispose of misfolded proteins in the endoplasmic reticulum of adipocytes.

Shuangcheng Alivia Wu, Chenchen Shen, Xiaoqiong Wei, Xiawei Zhang, Siwen Wang, Xinxin Chen, Mauricio Torres, You Lu, Liangguang Leo Lin, Huilun Helen Wang, Allen H Hunter, Deyu Fang, Shengyi Sun, Magdalena I Ivanova, Yi Lin, Ling Qi.

Endoplasmic reticulum (ER)-associated degradation (ERAD) and ER-phagy are two principal degradative mechanisms for ER proteins and aggregates, respectively; however, the crosstalk between these two pathways under physiological settings remains unexplored. Using adipocytes as a model system, here we report that SEL1L-HRD1 protein complex of ERAD degrades misfolded ER proteins and limits ER-phagy and that, only when SEL1L-HRD1 ERAD is impaired, the ER becomes fragmented and cleared by ER-phagy. When both are compromised, ER fragments containing misfolded proteins spatially coalesce into a distinct architecture termed Coalescence of ER Fragments (CERFs), consisted of lipoprotein lipase (LPL, a key lipolytic enzyme and an endogenous SEL1L-HRD1 substrate) and certain ER chaperones. CERFs enlarge and become increasingly insoluble with age. Finally, we reconstitute the CERFs through LPL and BiP phase separation in vitro, a process influenced by both redox environment and C-terminal tryptophan loop of LPL. Hence, our findings demonstrate a sequence of events centered around SEL1L-HRD1 ERAD to dispose of misfolded proteins in the ER of adipocytes, highlighting the profound cellular adaptability to misfolded proteins in the ER in vivo.

DOI: https://doi.org/10.1038/s41467-023-38690-4
Calcif Tissue Int. 2023 May 27.

Bone and the Unfolded Protein Response: In Sickness and in Health.

Srividhya Iyer, Douglas J Adams.

  Differentiation and optimal function of osteoblasts and osteoclasts are contingent on synthesis and maintenance of a healthy proteome. Impaired and/or altered secretory capacity of these skeletal cells is a primary driver of most skeletal diseases. The endoplasmic reticulum (ER) orchestrates the folding and maturation of membrane as well as secreted proteins at high rates within a calcium rich and oxidative organellar niche. Three ER membrane proteins monitor fidelity of protein processing in the ER and initiate an intricate signaling cascade known as the Unfolded Protein Response (UPR) to remediate accumulation of misfolded proteins in its lumen, a condition referred to as ER stress. The UPR aids in fine-tuning, expanding and/or modifying the cellular proteome, especially in specialized secretory cells, to match everchanging physiologic cues and metabolic demands. Sustained activation of the UPR due to chronic ER stress, however, is known to hasten cell death and drive pathophysiology of several diseases. A growing body of evidence suggests that ER stress and an aberrant UPR may contribute to poor skeletal health and the development of osteoporosis. Small molecule therapeutics that target distinct components of the UPR may therefore have implications for developing novel treatment modalities relevant to the skeleton. This review summarizes the complexity of UPR actions in bone cells in the context of skeletal physiology and osteoporotic bone loss, and highlights the need for future mechanistic studies to develop novel UPR therapeutics that mitigate adverse skeletal outcomes.

Keywords:  ATF6; ER stress; IRE1; PERK; Protein misfolding; Proteostasis

DOI:  https://doi.org/10.1007/s00223-023-01096-x
Respir Res. 2023 Jun 02. 24(1): 149

HMGB1-induced activation of ER stress contributes to pulmonary artery hypertension in vitro and in vivo.

Qianqian Zhang, Yuqian Chen, Qingting Wang, Yan Wang, Wei Feng, Limin Chai, Jin Liu, Danyang Li, Huan Chen, Yuanjie Qiu, Nirui Shen, Xiangyu Shi, Xinming Xie, Manxiang Li.

   BACKGROUND: HMGB1 and ER stress have been considered to participate in the progression of pulmonary artery hypertension (PAH). However, the molecular mechanism underlying HMGB1 and ER stress in PAH remains unclear. This study aims to explore whether HMGB1 induces pulmonary artery smooth muscle cells (PASMCs) functions and pulmonary artery remodeling through ER stress activation.
METHODS: Primary cultured PASMCs and monocrotaline (MCT)-induced PAH rats were applied in this study. Cell proliferation and migration were determined by CCK-8, EdU and transwell assay. Western blotting was conducted to detect the protein levels of protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor-4 (ATF4), seven in absentia homolog 2 (SIAH2) and homeodomain interacting protein kinase 2 (HIPK2). Hemodynamic measurements, immunohistochemistry staining, hematoxylin and eosin staining were used to evaluate the development of PAH. The ultrastructure of ER was observed by transmission electron microscopy.
RESULTS: In primary cultured PASMCs, HMGB1 reduced HIPK2 expression through upregulation of ER stress-related proteins (PERK and ATF4) and subsequently increased SIAH2 expression, which ultimately led to PASMC proliferation and migration. In MCT-induced PAH rats, interfering with HMGB1 by glycyrrhizin, suppression of ER stress by 4-phenylbutyric acid or targeting SIAH2 by vitamin K3 attenuated the development of PAH. Additionally, tetramethylpyrazine (TMP), as a component of traditional Chinese herbal medicine, reversed hemodynamic deterioration and vascular remodeling by targeting PERK/ATF4/SIAH2/HIPK2 axis.
CONCLUSIONS: The present study provides a novel insight to understand the pathogenesis of PAH and suggests that targeting HMGB1/PERK/ATF4/SIAH2/HIPK2 cascade might have potential therapeutic value for the prevention and treatment of PAH.

Keywords:  ER stress; HMGB1; Pulmonary artery hypertension; Tetramethylpyrazine

DOI:  https://doi.org/10.1186/s12931-023-02454-x
Heliyon. 2023 May;9(5): e16246

Non-coding RNA mediates endoplasmic reticulum stress-induced apoptosis in heart disease.

Mingyuan Fan, Jing Zhang, Lei Zeng, Danpeng Wang, Jiao Chen, Xiaorong Xi, Jing Long, Jinzhu Huang, Xueping Li.

  Apoptosis is a complex and highly self-regulating form of cell death, which is an important cause of the continuous decline in ventricular function and is widely involved in the occurrence and development of heart failure, myocardial infarction, and myocarditis. Endoplasmic reticulum stress plays a crucial role in apoptosis-inducing. Accumulation of misfolded or unfolded proteins causes cells to undergo a stress response called unfolded protein response (UPR). UPR initially has a cardioprotective effect. Nevertheless, prolonged and severe ER stress will lead up to apoptosis of stressed cells. Non-coding RNA is a type of RNA that does not code proteins. An ever-increasing number of studies have shown that non-coding RNAs are involved in regulating endoplasmic reticulum stress-induced cardiomyocyte injury and apoptosis. In this study, the effects of miRNA and LncRNA on endoplasmic reticulum stress in various heart diseases were mainly discussed to clarify their protective effects and potential therapeutic strategies for apoptosis.

Keywords:  Apoptosis; Endoplasmic reticulum stress; Heart disease; Ischemia/reperfusion; Non-coding RNA; microRNA

DOI:  https://doi.org/10.1016/j.heliyon.2023.e16246
ACS Nano. 2023 May 31.

A Native Drug-Free Macromolecular Therapeutic to Trigger Mutual Reinforcing of Endoplasmic Reticulum Stress and Mitochondrial Dysfunction for Cancer Treatment.

Wenhui Wang, Yongteng Zhang, Zeshu Wang, Xueping Liu, Siyu Lu, Xianglong Hu.

  Drug-free macromolecular therapeutics are promising alternatives to traditional drugs. Nanomedicines with multiple organelles targeting can potentially increase the efficacy. Herein, a drug-free macromolecular therapeutic was designed to formulate endoplasmic reticulum (ER) and mitochondria dual-targeting nanoparticles (EMT-NPs), which can synergistically elicit ER stress and mitochondrial dysfunction. In vitro experiments indicated that EMT-NPs could effectively enter ER and mitochondria at an approximate ratio of 2 to 3. Subsequently, EMT-NPs could upregulate ER stress-related protein expression (IRE1α, CHOP), boosting calcium ion (Ca2+) efflux and activating the caspase-12 signaling cascade in cancer cells. In addition, EMT-NPs induced direct oxidative stress in mitochondria; some mitochondrial-related apoptotic events such as decreased mitochondrial membrane potential (MMP), upregulation of Bax, cytochrome c release, and caspase-3 activation were also observed for tumor cells upon incubation with EMT-NPs. Furthermore, the leaked Ca2+ from ER could induce mitochondrial Ca2+ overloading to further augment cancer cell apoptosis. In brief, mitochondrial and ER signaling networks collaborated well to promote cancer cell death. Extended photoacoustic and fluorescence imaging served well for the treatment of in vivo patient-derived xenografts cancer model. This drug-free macromolecular strategy with multiple subcellular targeting provides a potential paradigm for cancer theranostics in precision nanomedicine.

Keywords:  cancer therapy; drug-free macromolecular therapeutics; endoplasmic reticulum; mitochondria; patient-derived xenografts cancer

DOI:  https://doi.org/10.1021/acsnano.3c03450
Toxicol Sci. 2023 Jun 01. pii: kfad055. [Epub ahead of print]

ATF6 is a critical regulator of cadmium-mediated apoptosis in spermatocytes.

Sung Woo Lee, Bokyung Kim, Jung Bae Seong, Young-Ho Park, Hong Jun Lee, Dong-Seok Lee.

  In this study, we examined the mechanisms of cadmium exposure-induced endoplasmic reticulum (ER) stress response and apoptosis in spermatocytes. Responses to cadmium toxicity were investigated using spermatocytes overexpressing p50ATF6, ATF4, and spliced XBP1s, belonging to the three unfolded protein response (UPR) pathways. The ER stress and apoptosis response to cadmium were most strongly stimulated through the activating transcription factor 6 (ATF6) pathway; in contrast, siRNA-induced inhibition of protein expression could reduce apoptosis under stressful conditions. An in vivo experiment using mice confirmed that upregulation of p50ATF6 in the testis increased apoptosis in response to cadmium exposure. Further, when confirming the correlation between ER stress and MAPK in cadmium toxicity, p38 MAPK phosphorylation was strongly regulated by p50ATF6; p-p38 also mediated the activity of p50ATF6. Overall, these findings suggest that modulating the activity of p38 MAPK and p50ATF6 in cadmium exposure-induced toxicity can be considered a potential strategy to treat infertility.

Keywords:  ATF6; apoptosis; cadmium; endoplasmic reticulum (ER) stress; spermatocyte

DOI:  https://doi.org/10.1093/toxsci/kfad055
Front Immunol. 2023 ;14 1152336

Role of endoplasmic reticulum autophagy in acute lung injury.

Shiping Liu, Xiaoyu Fang, Ruiyao Zhu, Jing Zhang, Huijuan Wang, Jiaxi Lei, Chaoqun Wang, Lu Wang, Liying Zhan.

  Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), the prime causes of morbidity and mortality in critically ill patients, are usually treated by general supportive treatments. Endoplasmic reticulum autophagy (ER-phagy) maintains cellular homeostasis by degrading damaged endoplasmic reticulum (ER) fragments and misfolded proteins. ER-phagy is crucial for maintaining ER homeostasis and improving the internal environment. ER-phagy has a particular role in some aspects, such as immunity, inflammation, cell death, pathogen infection, and collagen quality. In this review, we summarized the definition, epidemiology, and pathophysiology of ALI/ARDS and described the regulatory mechanisms and functions of ER-phagy as well as discussed the potential role of ER-phagy in ALI/ARDS from the perspectives of immunity, inflammation, apoptosis, pathogen infection, and fibrosis to provide a novel and effective target for improving the prognosis of ALI/ARDS.

Keywords:  ALI; ARDS; ER stress; ER-phagy; ER-phagy receptor; immunity; inflammation

DOI:  https://doi.org/10.3389/fimmu.2023.1152336
Front Cell Infect Microbiol. 2023 ;13 1135203

Role of UPRmt and mitochondrial dynamics in host immunity: it takes two to tango.

Manmohan Kumar, Shagun Sharma, Shibnath Mazumder.

  The immune system of a host contains a group of heterogeneous cells with the prime aim of restraining pathogenic infection and maintaining homeostasis. Recent reports have proved that the various subtypes of immune cells exploit distinct metabolic programs for their functioning. Mitochondria are central signaling organelles regulating a range of cellular activities including metabolic reprogramming and immune homeostasis which eventually decree the immunological fate of the host under pathogenic stress. Emerging evidence suggests that following bacterial infection, innate immune cells undergo profound metabolic switching to restrain and countervail the bacterial pathogens, promote inflammation and restore tissue homeostasis. On the other hand, bacterial pathogens affect mitochondrial structure and functions to evade host immunity and influence their intracellular survival. Mitochondria employ several mechanisms to overcome bacterial stress of which mitochondrial UPR (UPRmt) and mitochondrial dynamics are critical. This review discusses the latest advances in our understanding of the immune functions of mitochondria against bacterial infection, particularly the mechanisms of mitochondrial UPRmt and mitochondrial dynamics and their involvement in host immunity.

Keywords:  ATFS-1; DRP1; MFN1; MFN2; UPRmt; bacterial infection; mitochondrial dynamics

DOI:  https://doi.org/10.3389/fcimb.2023.1135203