bims-unfpre 2023-03-05 papers

Issue of 2023–03–05
five papers selected by
Susan Logue, University of Manitoba

Cell Rep. 2023 Mar 03. pii: S2211-1247(23)00220-6. [Epub ahead of print]42(3): 112209

VMP1 affects endoplasmic reticulum stress sensitivity via differential modulation of the three unfolded protein response arms.

Tao Li, Hongyu Zhao, Gaofeng Guo, Shuwei Xia, Likun Wang.

Consisting of three signaling pathways, the unfolded protein response (UPR) can be either protective or detrimental to cells that undergo ER stress. Elaborate regulation of the UPR is key to the cell-fate decision, but how it is achieved remains vague. Here, by studying cells deficient in vacuole membrane protein 1 (VMP1), a UPR regulator, we report a model of UPR regulation in which the three pathways are divergently controlled. Under basal conditions, calcium binding specifically activates PERK. Under ER stress, ER-mitochondria interaction-induced mitochondrial stress cooperates with PERK to suppress IRE1α and ATF6 by decelerating global protein synthesis. Such sophisticated regulation commits limited activation of the UPR yet refrains from UPR hyperactivation, protecting cells from chronic ER stress despite decreasing cell proliferation. Therefore, our study reveals interorganelle-interaction-dependent and calcium-dependent regulation of the UPR that dictates cell fate.

Keywords: CP: Cell biology; ER stress; ER stress resistance; ER-mitochondria contact; VMP1; calcium; integrated stress response; mitochondrial stress; unfolded protein response

DOI: https://doi.org/10.1016/j.celrep.2023.112209

Cell Death Dis. 2023 Feb 27. 14(2): 166

The UDPase ENTPD5 regulates ER stress-associated renal injury by mediating protein N-glycosylation.

Impaired protein N-glycosylation leads to the endoplasmic reticulum (ER) stress, which triggers adaptive survival or maladaptive apoptosis in renal tubules in diabetic kidney disease (DKD). Therapeutic strategies targeting ER stress are promising for the treatment of DKD. Here, we report a previously unappreciated role played by ENTPD5 in alleviating renal injury by mediating ER stress. We found that ENTPD5 was highly expressed in normal renal tubules; however, ENTPD5 was dynamically expressed in the kidney and closely related to pathological DKD progression in both human patients and mouse models. Overexpression of ENTPD5 relieved ER stress in renal tubular cells, leading to compensatory cell proliferation that resulted in hypertrophy, while ENTPD5 knockdown aggravated ER stress to induce cell apoptosis, leading to renal tubular atrophy and interstitial fibrosis. Mechanistically, ENTPD5-regulated N-glycosylation of proteins in the ER to promote cell proliferation in the early stage of DKD, and continuous hyperglycemia activated the hexosamine biosynthesis pathway (HBP) to increase the level of UDP-GlcNAc, which driving a feedback mechanism that inhibited transcription factor SP1 activity to downregulate ENTPD5 expression in the late stage of DKD. This study was the first to demonstrate that ENTPD5 regulated renal tubule cell numbers through adaptive proliferation or apoptosis in the kidney by modulating the protein N-glycosylation rate in the ER, suggesting that ENTPD5 drives cell fate in response to metabolic stress and is a potential therapeutic target for renal diseases.

DOI: https://doi.org/10.1038/s41419-023-05685-4

Food Chem Toxicol. 2023 Feb 28. pii: S0278-6915(23)00102-3. [Epub ahead of print] 113700

Taurine reduces apoptosis mediated by endoplasmic reticulum stress in islet β-cells induced by high-fat and -glucose diets.

Dongdong Zhao, Xiaozhou Zhang, Yongxin Bian, Lu Meng, Yutong Wu, Yidi Ma, Chen Li, Jingjing Wang, Zizheng Fu, Jingyuan Dai, Deqi Yin, Shumei Lin, Jianmin Hu.

Poor eating habits, especially high-fat and -glucose diets intake, can lead to endoplasmic reticulum (ER) stress in islet β-cells, insulin resistance, and islet β-cell dysfunction and cause islet β-cell apoptosis, which leads to type 2 diabetes mellitus (T2DM). Taurine is a crucial amino acid in the human body. In this study, we aimed to explore the mechanism through which taurine reduces glycolipid toxicity. INS-1 islet β-cell lines were cultured with a high concentration of fat and glucose. SD rats were fed a high-fat and -glucose diet. MTS, Transmission electron microscopy, Flow cytometry, Hematoxylin-eosin, TUNEL, Western blotting analysis and other methods were used to detect relevant indicators. The research found that taurine increases the cell activity, reduces the apoptosis rate, alleviates the structural changes of ER under high-fat and -glucose exposure models. In addition, taurine improves blood lipid content and islets pathological changes, regulates the relative protein expression in ER stress and apoptosis, increases the insulin sensitivity index (HOMA-IS), and reduces the insulin resistance index (HOMAC-IR) of SD rats fed with a high-fat and -glucose diet.

Keywords: Apoptosis; Endoplasmic reticulum stress; Glucolipotoxicity; Islet β-cells; Taurine; Type 2 diabetes mellitus

DOI: https://doi.org/10.1016/j.fct.2023.113700

Front Genet. 2023 ;14 1097571

Identification of long non-coding RNA and circular RNA associated networks in cellular stress responses.

Xiuzhi Li, Jingxin Li, Ge Shan, Xiaolin Wang.

Mammalian cells employ various adaptive responses to cope with multiple stresses to maintain homeostasis. Functional roles of non-coding RNAs (ncRNAs) in response to cellular stresses have been proposed, and systematical investigations about the crosstalk among distinct types of RNAs are required. Here, we challenged HeLa cells with thapsigargin (TG) and glucose deprivation (GD) treatments to induce endoplasmic reticulum (ER) and metabolic stresses, respectively. Ribosomal RNA (rRNA)-depleted RNA sequencing (RNA-seq) was then performed. Characterization of the RNA-seq data revealed a series of differentially expressed long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) with parallel changes responsive to both stimuli. We further constructed the lncRNA/circRNA-mRNA co-expressing network, competing endogenous RNA (ceRNA) network in the lncRNA/circRNA-miRNA-mRNA axis, and lncRNA/circRNA-RNA binding protein (RBP) interactome map. These networks indicated the potential cis and/or trans regulatory roles of lncRNAs and circRNAs. Moreover, Gene Ontology analysis demonstrated that these identified ncRNAs were associated with several essential biological processes known to be related to cellular stress responses. In conclusion, we systematically established functional regulatory networks of lncRNA/circRNA-mRNA, lncRNA/circRNA-miRNA-mRNA and lncRNA/circRNA-RBP to perceive the potential interactions and biological processes during cellular stresses. These results provided insights in ncRNA regulatory networks of stress responses and the basis for further identification of pivotal factors involved in cellular stress responses.

Keywords: RBP; ceRNA; circRNA; er stress; glucose deprivation; lncRNA; miRNA; network

DOI: https://doi.org/10.3389/fgene.2023.1097571