bims-ershed 2021-07-25 papers

Issue of 2021‒07‒25
five papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

Int J Oncol. 2021 Aug;pii: 60. [Epub ahead of print]59(2):

Endoplasmic reticulum stress‑induced cell death as a potential mechanism for targeted therapy in glioblastoma (Review).

Pengfei Shi, Zhuohang Zhang, Jie Xu, Li Zhang, Hongjuan Cui.

The endoplasmic reticulum (ER) is an essential organelle for protein synthesis, folding and modification, lipid synthesis, and calcium storage. When endogenous or exogenous stimuli lead to ER‑synthesized protein folding dysfunction, numerous unfolded or misfolded proteins accumulate in the ER cavity and cause a series of subsequent responses, referred to as ER stress. If ER stress is continuous, the unfolded protein response (UPR) is not enough to remove the accumulated unfolded and misfolded proteins, and thus, UPR signaling pathways will drive cell apoptosis. Glioblastoma (GBM) is currently the most aggressive and common malignant tumor of the nervous system. Since ER stress may increase the sensitivity of GBM to temozolomide, this article reviews the possible mechanisms of ER stress‑induced apoptosis and the factors affecting ER stress, and evaluates the potential of ER stress as a therapeutic target.

Keywords: apoptosis; compounds; endoplasmic reticulum stress; glioblastoma; unfolded protein response

DOI: https://doi.org/10.3892/ijo.2021.5240

J Cell Physiol. 2021 Jul 23.

IRE1 signaling regulates chondrocyte apoptosis and death fate in the osteoarthritis.

Rongxiang Huang, Zhang Hui, Sun Wei, Duan Li, Wencui Li, Wang Daping, Murad Alahdal.

IRE1 is an important central regulator of unfolded protein response (UPR) in the endoplasmic reticulum (ER) because of its ability to regulate cell fate as a function of stress sensing. When misfolded proteins accumulated in chondrocytes ER, IRE1 disintegrates with BIP/GRP78 and undergoes dimer/oligomerization and transautophosphorylation. These two processes are mediated through an enzyme activity of IRE1 to activate endoribonuclease and generates XBP1 by unconventional splicing of XBP1 messenger RNA. Thereby promoting the transcription of UPR target genes and apoptosis. The deficiency of inositol-requiring enzyme 1α (IRE1α) in chondrocytes downregulates prosurvival factors XBP1S and Bcl-2, which enhances the apoptosis of chondrocytes through increasing proapoptotic factors caspase-3, p-JNK, and CHOP. Meanwhile, the activation of IRE1α increases chondrocyte viability and reduces cell apoptosis. However, the understanding of IRE1 responses and cell death fate remains controversial. This review provides updated data about the role IRE1 plays in chondrocytes and new insights about the potential efficacy of IRE1 regulation in cartilage repair and osteoarthritis treatment.

Keywords: ERS; IRE1; apoptosis; chondrocyte; osteoarthritis

DOI: https://doi.org/10.1002/jcp.30537

Mol Cells. 2021 Jul 23.

Endoplasmic Reticulum Stress Induces CAP2 Expression Promoting Epithelial-Mesenchymal Transition in Liver Cancer Cells.

Sarah Yoon, Boram Shin, Hyun Goo Woo.

Cyclase-associated protein 2 (CAP2) has been addressed as a candidate biomarker in various cancer types. Previously, we have shown that CAP2 is expressed during multi-step hepatocarcinogenesis; however, its underlying mechanisms in liver cancer cells are not fully elucidated yet. Here, we demonstrated that endoplasmic reticulum (ER) stress induced CAP2 expression, and which promoted migration and invasion of liver cancer cells. We also found that the ER stress-induced CAP2 expression is mediated through activation of protein kinase C epsilon (PKCε) and the promotor binding of activating transcription factor 2 (ATF2). In addition, we further demonstrated that CAP2 expression promoted epithelial-mesenchymal transition (EMT) through activation of Rac1 and ERK. In conclusion, we suggest that ER stress induces CAP2 expression promoting EMT in liver cancers cells. Our results shed light on the novel functions of CAP2 in the metastatic process of liver cancer cells.

Keywords: activating transcription factor 2; cyclase-associated protein 2; endoplasmic reticulum-stress; epithelial-mesenchymal transition; extracellular signal-regulated kinase; hepatocellular catcinoma; protein kinase C epsilon

DOI: https://doi.org/10.14348/molcells.2021.0031

J Clin Invest. 2021 Jul 20. pii: 143737. [Epub ahead of print]

IRE1α regulates skeletal muscle regeneration through Myostatin mRNA decay.

Shengqi He, Tingting Fu, Yue Yu, Qinhao Liang, Luyao Li, Jing Liu, Xuan Zhang, Qian Zhou, Qiqi Guo, Dengqiu Xu, Yong Chen, Xiaolong Wang, Yulin Chen, Jianmiao Liu, Zhenji Gan, Yong Liu.

Skeletal muscle can undergo a regenerative process from injury or disease to preserve muscle mass and function, which is critically influenced by cellular stress responses. Inositol-requiring enzyme 1 (IRE1) is an ancient endoplasmic reticulum (ER) stress sensor and mediates a key branch of the unfolded protein response (UPR). In mammals, IRE1α is implicated in the homeostatic control of stress responses during tissue injury and regeneration. Here, we show that IRE1α serves as a myogenic regulator in skeletal muscle regeneration in response to injury and muscular dystrophy. We found in mice that IRE1α was activated during injury-induced muscle regeneration, and muscle-specific IRE1α ablation resulted in impaired regeneration upon cardiotoxin-induced injury. Gain- and loss-of-function studies in myocytes demonstrated that IRE1αacts to sustain both differentiation in myoblasts and hypertrophy in myotubes through regulated IRE1-dependent decay (RIDD) of mRNA encoding Myostatin, a key negative regulator of muscle repair and growth. Furthermore, in the mouse model of Duchenne muscular dystrophy (DMD), loss of muscle IRE1α resulted in augmented Myostatin signaling and exacerbated the dystrophic phenotypes. Thus, these results reveal a pivotal role for the RIDD output of IRE1α in muscle regeneration, offering new insight into potential therapeutic strategies for muscle loss diseases.

Keywords: Cell stress; Molecular pathology; Muscle Biology; Skeletal muscle

DOI: https://doi.org/10.1172/JCI143737

Cell Rep. 2021 Jul 20. pii: S2211-1247(21)00820-2. [Epub ahead of print]36(3): 109407

Alternative 3' UTRs play a widespread role in translation-independent mRNA association with the endoplasmic reticulum.

Larry C Cheng, Dinghai Zheng, Qiang Zhang, Aysegul Guvenek, Hong Cheng, Bin Tian.

Transcripts encoding membrane and secreted proteins are known to associate with the endoplasmic reticulum (ER) through translation. Here, using cell fractionation, polysome profiling, and 3' end sequencing, we show that transcripts differ substantially in translation-independent ER association (TiERA). Genes in certain functional groups, such as cell signaling, tend to have significantly higher TiERA potentials than others, suggesting the importance of ER association for their mRNA metabolism, such as localized translation. The TiERA potential of a transcript is determined largely by size, sequence content, and RNA structures. Alternative polyadenylation (APA) isoforms can have distinct TiERA potentials because of changes in transcript features. The widespread 3' UTR lengthening in cell differentiation leads to greater transcript association with the ER, especially for genes that are capable of expressing very long 3' UTRs. Our data also indicate that TiERA is in dynamic competition with translation-dependent ER association, suggesting limited space on the ER for mRNA association.

Keywords: 3′ UTR; RNA structure; alternative 3′UTR; alternative polyadenylation; cell differentiation; endoplasmic reticulum; mRNA subcellular localization; myogenesis

DOI: https://doi.org/10.1016/j.celrep.2021.109407