bims-unfpre 2024-08-04 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2024‒08‒04
nine papers selected by
Susan Logue, University of Manitoba

A genome-wide CRISPR/Cas9 screen identifies calreticulin as a selective repressor of ATF6α.
Sestrin2 drives ER-phagy in response to protein misfolding.
Long non-coding RNA-mediated modulation of endoplasmic reticulum stress under pathological conditions.
Triggering of endoplasmic reticulum stress via ATF4-SPHK1 signaling promotes glioblastoma invasion and chemoresistance.
The IRE1α pathway in glomerular diseases: The unfolded protein response and beyond.
Recent progress of endoplasmic reticulum stress in the mechanism of atherosclerosis.
Endoplasmic reticulum stress-a key guardian in cancer.
Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in obesity.
The endoplasmic reticulum pool of Bcl-xL prevents cell death through IP3R-dependent calcium release.

Elife. 2024 Jul 29. pii: RP96979. [Epub ahead of print]13

A genome-wide CRISPR/Cas9 screen identifies calreticulin as a selective repressor of ATF6α.

Joanne Tung, Lei Huang, Ginto George, Heather P Harding, David Ron, Adriana Ordonez.

  Activating transcription factor 6 (ATF6) is one of three endoplasmic reticulum (ER) transmembrane stress sensors that mediate the unfolded protein response (UPR). Despite its crucial role in long-term ER stress adaptation, regulation of ATF6 alpha (α) signalling remains poorly understood, possibly because its activation involves ER-to-Golgi and nuclear trafficking. Here, we generated an ATF6α/Inositol-requiring kinase 1 (IRE1) dual UPR reporter CHO-K1 cell line and performed an unbiased genome-wide CRISPR/Cas9 mutagenesis screen to systematically profile genetic factors that specifically contribute to ATF6α signalling in the presence and absence of ER stress. The screen identified both anticipated and new candidate genes that regulate ATF6α activation. Among these, calreticulin (CRT), a key ER luminal chaperone, selectively repressed ATF6α signalling: Cells lacking CRT constitutively activated a BiP::sfGFP ATF6α-dependent reporter, had higher BiP levels and an increased rate of trafficking and processing of ATF6α. Purified CRT interacted with the luminal domain of ATF6α in vitro and the two proteins co-immunoprecipitated from cell lysates. CRT depletion exposed a negative feedback loop implicating ATF6α in repressing IRE1 activity basally and overexpression of CRT reversed this repression. Our findings indicate that CRT, beyond its known role as a chaperone, also serves as an ER repressor of ATF6α to selectively regulate one arm of the UPR.

Keywords:  ATF6⍺; CHO-K1 cells; CRT; UPR; calreticulin; cell biology; endoplasmic reticulum; genome-wide CRISPR/Cas9 screen; unfolded protein response

DOI:  https://doi.org/10.7554/eLife.96979
Dev Cell. 2024 Jul 30. pii: S1534-5807(24)00441-6. [Epub ahead of print]

Sestrin2 drives ER-phagy in response to protein misfolding.

Chiara De Leonibus, Marianna Maddaluno, Rosa Ferriero, Roberta Besio, Laura Cinque, Pei Jin Lim, Alessandro Palma, Rossella De Cegli, Salvatore Gagliotta, Sandro Montefusco, Maria Iavazzo, Marianne Rohrbach, Cecilia Giunta, Elena Polishchuk, Diego Louis Medina, Diego Di Bernardo, Antonella Forlino, Pasquale Piccolo, Carmine Settembre.

  Protein biogenesis within the endoplasmic reticulum (ER) is crucial for organismal function. Errors during protein folding necessitate the removal of faulty products. ER-associated protein degradation and ER-phagy target misfolded proteins for proteasomal and lysosomal degradation. The mechanisms initiating ER-phagy in response to ER proteostasis defects are not well understood. By studying mouse primary cells and patient samples as a model of ER storage disorders (ERSDs), we show that accumulation of faulty products within the ER triggers a response involving SESTRIN2, a nutrient sensor controlling mTORC1 signaling. SESTRIN2 induction by XBP1 inhibits mTORC1's phosphorylation of TFEB/TFE3, allowing these transcription factors to enter the nucleus and upregulate the ER-phagy receptor FAM134B along with lysosomal genes. This response promotes ER-phagy of misfolded proteins via FAM134B-Calnexin complex. Pharmacological induction of FAM134B improves clearance of misfolded proteins in ERSDs. Our study identifies the interplay between nutrient signaling and ER quality control, suggesting therapeutic strategies for ERSDs.

Keywords:  ER storage disorders; ER-phagy; FAM134B; TFEB; alpha(1)-antitrypsin Z (alpha(1)-ATZ); autophagy; collagen; endoplasmic reticulum; mTORC1; quality control

DOI:  https://doi.org/10.1016/j.devcel.2024.07.004
J Cell Mol Med. 2024 Jul;28(14): e18561

Long non-coding RNA-mediated modulation of endoplasmic reticulum stress under pathological conditions.

Yusuf Cem Çiftçi, Yiğit Yurtsever, Bünyamin Akgül.

  Endoplasmic reticulum (ER) stress, which ensues from an overwhelming protein folding capacity, activates the unfolded protein response (UPR) in an effort to restore cellular homeostasis. As ER stress is associated with numerous diseases, it is highly important to delineate the molecular mechanisms governing the ER stress to gain insight into the disease pathology. Long non-coding RNAs, transcripts with a length of over 200 nucleotides that do not code for proteins, interact with proteins and nucleic acids, fine-tuning the UPR to restore ER homeostasis via various modes of actions. Dysregulation of specific lncRNAs is implicated in the progression of ER stress-related diseases, presenting these molecules as promising therapeutic targets. The comprehensive analysis underscores the importance of understanding the nuanced interplay between lncRNAs and ER stress for insights into disease mechanisms. Overall, this review consolidates current knowledge, identifies research gaps and offers a roadmap for future investigations into the multifaceted roles of lncRNAs in ER stress and associated diseases to shed light on their pivotal roles in the pathogenesis of related diseases.

Keywords:  ATF6; IRE1; PERK; disease; endoplasmic reticulum stress; long non‐coding RNAs; unfolded protein response

DOI:  https://doi.org/10.1111/jcmm.18561
Cell Death Dis. 2024 Aug 01. 15(8): 552

Triggering of endoplasmic reticulum stress via ATF4-SPHK1 signaling promotes glioblastoma invasion and chemoresistance.

Beiwu Lan, Zhoudao Zhuang, Jinnan Zhang, Yichun He, Nan Wang, Zhuoyue Deng, Lin Mei, Yan Li, Yufei Gao.

Despite advances in therapies, glioblastoma (GBM) recurrence is almost inevitable due to the aggressive growth behavior of GBM cells and drug resistance. Temozolomide (TMZ) is the preferred drug for GBM chemotherapy, however, development of TMZ resistance is over 50% cases in GBM patients. To investigate the mechanism of TMZ resistance and invasive characteristics of GBM, analysis of combined RNA-seq and ChIP-seq was performed in GBM cells in response to TMZ treatment. We found that the PERK/eIF2α/ATF4 signaling was significantly upregulated in the GBM cells with TMZ treatment, while blockage of ATF4 effectively inhibited cell migration and invasion. SPHK1 expression was transcriptionally upregulated by ATF4 in GBM cells in response to TMZ treatment. Blockage of ATF4-SPHK1 signaling attenuated the cellular and molecular events in terms of invasive characteristics and TMZ resistance. In conclusion, GBM cells acquired chemoresistance in response to TMZ treatment via constant ER stress. ATF4 transcriptionally upregulated SPHK1 expression to promote GBM cell aggression and TMZ resistance. The ATF4-SPHK1 signaling in the regulation of the transcription factors of EMT-related genes could be the underlying mechanism contributing to the invasion ability of GBM cells and TMZ resistance. ATF4-SPHK1-targeted therapy could be a potential strategy against TMZ resistance in GBM patients.

DOI: https://doi.org/10.1038/s41419-024-06936-8
Front Mol Med. 2022 ;2 971247

The IRE1α pathway in glomerular diseases: The unfolded protein response and beyond.

José R Navarro-Betancourt, Andrey V Cybulsky.

  Endoplasmic reticulum (ER) function is vital for protein homeostasis ("proteostasis"). Protein misfolding in the ER of podocytes (glomerular visceral epithelial cells) is an important contributor to the pathogenesis of human glomerular diseases. ER protein misfolding causes ER stress and activates a compensatory signaling network called the unfolded protein response (UPR). Disruption of the UPR, in particular deletion of the UPR transducer, inositol-requiring enzyme 1α (IRE1α) in mouse podocytes leads to podocyte injury and albuminuria in aging, and exacerbates injury in glomerulonephritis. The UPR may interact in a coordinated manner with autophagy to relieve protein misfolding and its consequences. Recent studies have identified novel downstream targets of IRE1α, which provide new mechanistic insights into proteostatic pathways. Novel pathways of IRE1α signaling involve reticulophagy, mitochondria, metabolism, vesicular trafficking, microRNAs, and others. Mechanism-based therapies for glomerulopathies are limited, and development of non-invasive ER stress biomarkers, as well as targeting ER stress with pharmacological compounds may represent a therapeutic opportunity for preventing or attenuating progression of chronic kidney disease.

Keywords:  autophagy; cell injury; endoplasmic reticulum; glomerulonephitis; podocyte

DOI:  https://doi.org/10.3389/fmmed.2022.971247
Front Cardiovasc Med. 2024 ;11 1413441

Recent progress of endoplasmic reticulum stress in the mechanism of atherosclerosis.

Lin Ni, Luqun Yang, Yuanyuan Lin.

  The research progress of endoplasmic reticulum (ER) stress in atherosclerosis (AS) is of great concern. The ER, a critical cellular organelle, plays a role in important biological processes including protein synthesis, folding, and modification. Various pathological factors may cause ER stress, and sustained or excessive ER stress triggers the unfolded protein response, ultimately resulting in apoptosis and disease. Recently, researchers have discovered the importance of ER stress in the onset and advancement of AS. ER stress contributes to the occurrence of AS through different pathways such as apoptosis, inflammatory response, oxidative stress, and autophagy. Therefore, this review focuses on the mechanisms of ER stress in the development of AS and related therapeutic targets, which will contribute to a deeper understanding of the disease's pathogenesis and provide novel strategies for preventing and treating AS.

Keywords:  atherosclerosis; autophagy; cell apoptosis; endoplasmic reticulum stress; inflammatory; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.3389/fcvm.2024.1413441
Cell Death Discov. 2024 Jul 30. 10(1): 343

Endoplasmic reticulum stress-a key guardian in cancer.

Wenlong Zhang, Yidan Shi, Linda Oyang, Shiwen Cui, Shizhen Li, Jinyun Li, Lin Liu, Yun Li, Mingjing Peng, Shiming Tan, Longzheng Xia, Jinguan Lin, Xuemeng Xu, Nayiyuan Wu, Qiu Peng, Yanyan Tang, Xia Luo, Qianjin Liao, Xianjie Jiang, Yujuan Zhou.

Endoplasmic reticulum stress (ERS) is a cellular stress response characterized by excessive contraction of the endoplasmic reticulum (ER). It is a pathological hallmark of many diseases, such as diabetes, obesity, and neurodegenerative diseases. In the unique growth characteristic and varied microenvironment of cancer, high levels of stress are necessary to maintain the rapid proliferation and metastasis of tumor cells. This process is closely related to ERS, which enhances the ability of tumor cells to adapt to unfavorable environments and promotes the malignant progression of cancer. In this paper, we review the roles and mechanisms of ERS in tumor cell proliferation, apoptosis, metastasis, angiogenesis, drug resistance, cellular metabolism, and immune response. We found that ERS can modulate tumor progression via the unfolded protein response (UPR) signaling of IRE1, PERK, and ATF6. Targeting the ERS may be a new strategy to attenuate the protective effects of ERS on cancer. This manuscript explores the potential of ERS-targeted therapies, detailing the mechanisms through which ERS influences cancer progression and highlighting experimental and clinical evidence supporting these strategies. Through this review, we aim to deepen our understanding of the role of ER stress in cancer development and provide new insights for cancer therapy.

DOI: https://doi.org/10.1038/s41420-024-02110-3
bioRxiv. 2024 Jul 19. pii: 2024.07.17.603931. [Epub ahead of print]

Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in obesity.

Dan Wu, Venkateswararao Eeda, Zahra Maria, Komal Rawal, Oana Herlea-Pana, Ram Babu Undi, Hui-Ying Lim, Weidong Wang.

Overnutrition engenders the expansion of adipose tissue and the accumulation of immune cells, in particular, macrophages, in the adipose tissue, leading to chronic low-grade inflammation and insulin resistance. In obesity, several proinflammatory subpopulations of adipose tissue macrophages (ATMs) identified hitherto include the conventional "M1-like" CD11C-expressing ATM and the newly discovered metabolically activated CD9-expressing ATM; however, the relationship among ATM subpopulations is unclear. The ER stress sensor inositol-requiring enzyme 1α (IRE1α) is activated in the adipocytes and immune cells under obesity. It is unknown whether targeting IRE1α is capable of reversing insulin resistance and obesity and modulating the metabolically activated ATMs. We report that pharmacological inhibition of IRE1α RNase significantly ameliorates insulin resistance and glucose intolerance in diet-induced obesity mice. IRE1α inhibition also increases thermogenesis and energy expenditure, and hence protects against high fat diet-induced obesity. Our study shows that the "M1-like" CD11c+ ATMs are largely overlapping with but yet non-identical to CD9+ ATMs in obese white adipose tissue. Notably, IRE1α inhibition diminishes the accumulation of obesity-induced metabolically activated ATMs and "M1-like" ATMs, resulting in the curtailment of adipose inflammation and ensuing reactivation of thermogenesis, without augmentation of the alternatively activated M2 macrophage population. Our findings suggest the potential of targeting IRE1α for the therapeutic treatment of insulin resistance and obesity.

DOI: https://doi.org/10.1101/2024.07.17.603931
Cell Death Discov. 2024 Aug 01. 10(1): 346

The endoplasmic reticulum pool of Bcl-xL prevents cell death through IP3R-dependent calcium release.

Rudy Gadet, Lea Jabbour, Trang Thi Minh Nguyen, Olivier Lohez, Ivan Mikaelian, Philippe Gonzalo, Tomas Luyten, Mounira Chalabi-Dchar, Anne Wierinckx, Olivier Marcillat, Geert Bultynck, Ruth Rimokh, Nikolay Popgeorgiev, Germain Gillet.

Apoptosis plays a role in cell homeostasis in both normal development and disease. Bcl-xL, a member of the Bcl-2 family of proteins, regulates the intrinsic mitochondrial pathway of apoptosis. It is overexpressed in several cancers. Bcl-xL has a dual subcellular localisation and is found at the mitochondria as well as the endoplasmic reticulum (ER). However, the biological significance of its ER localisation is unclear. In order to decipher the functional contributions of the mitochondrial and reticular pools of Bcl-xL, we generated genetically modified mice expressing exclusively Bcl-xL at the ER, referred to as ER-xL, or the mitochondria, referred to as Mt-xL. By performing cell death assays, we demonstrated that ER-xL MEFs show increased vulnerability to apoptotic stimuli but are more resistant to ER stress. Furthermore, ER-xL MEFs displayed reduced 1,4,5-inositol trisphosphate receptor (IP3R)-mediated ER calcium release downstream of Phospholipase C activation. Collectively, our data indicate that upon ER stress, Bcl-xL negatively regulates IP3R-mediated calcium flux from the ER, which prevents ER calcium depletion and maintains the UPR and subsequent cell death in check. This work reveals a moonlighting function of Bcl-xL at the level of the ER, in addition to its well-known role in regulating apoptosis through the mitochondria.

DOI: https://doi.org/10.1038/s41420-024-02112-1