bims-unfpre 2024-07-14 papers

Issue of 2024‒07‒14
six papers selected by
Susan Logue, University of Manitoba

EMBO Rep. 2024 Jul 09.

The IRE1α/XBP1 signaling axis drives myoblast fusion in adult skeletal muscle.

Aniket S Joshi, Meiricris Tomaz da Silva, Anirban Roy, Tatiana E Koike, Mingfu Wu, Micah B Castillo, Preethi H Gunaratne, Yu Liu, Takao Iwawaki, Ashok Kumar.

Skeletal muscle regeneration involves a signaling network that regulates the proliferation, differentiation, and fusion of muscle precursor cells to injured myofibers. IRE1α, one of the arms of the unfolded protein response, regulates cellular proteostasis in response to ER stress. Here, we demonstrate that inducible deletion of IRE1α in satellite cells of mice impairs skeletal muscle regeneration through inhibiting myoblast fusion. Knockdown of IRE1α or its downstream target, X-box protein 1 (XBP1), also inhibits myoblast fusion during myogenesis. Transcriptome analysis revealed that knockdown of IRE1α or XBP1 dysregulates the gene expression of molecules involved in myoblast fusion. The IRE1α-XBP1 axis mediates the gene expression of multiple profusion molecules, including myomaker (Mymk). Spliced XBP1 (sXBP1) transcription factor binds to the promoter of Mymk gene during myogenesis. Overexpression of myomaker in IRE1α-knockdown cultures rescues fusion defects. Inducible deletion of IRE1α in satellite cells also inhibits myoblast fusion and myofiber hypertrophy in response to functional overload. Collectively, our study demonstrates that IRE1α promotes myoblast fusion through sXBP1-mediated up-regulation of the gene expression of multiple profusion molecules, including myomaker.

Keywords: IRE1; Muscle Regeneration; Myoblast Fusion; XBP1; and Myomaker

DOI: https://doi.org/10.1038/s44319-024-00197-4

Nat Commun. 2024 Jul 10. 15(1): 5804

Programmed cell death regulator BAP2 is required for IRE1-mediated unfolded protein response in Arabidopsis.

Noelia Pastor-Cantizano, Evan R Angelos, Cristina Ruberti, Tao Jiang, Xiaoyu Weng, Brandon C Reagan, Taslima Haque, Thomas E Juenger, Federica Brandizzi.

Environmental and physiological situations can challenge the balance between protein synthesis and folding capacity of the endoplasmic reticulum (ER) and cause ER stress, a potentially lethal condition. The unfolded protein response (UPR) restores ER homeostasis or actuates programmed cell death (PCD) when ER stress is unresolved. The cell fate determination mechanisms of the UPR are not well understood, especially in plants. Here, we integrate genetics and ER stress profiling with natural variation and quantitative trait locus analysis of 350 natural accessions of the model species Arabidopsis thaliana. Our analyses implicate a single nucleotide polymorphism to the loss of function of the general PCD regulator BON-ASSOCIATED PROTEIN2 (BAP2) in UPR outcomes. We establish that ER stress-induced BAP2 expression is antagonistically regulated by the UPR master regulator, inositol-requiring enzyme 1 (IRE1), and that BAP2 controls adaptive UPR amplitude in ER stress and ignites pro-death mechanisms in conditions of UPR insufficiency.

DOI: https://doi.org/10.1038/s41467-024-50105-6

iScience. 2024 Jul 19. 27(7): 110196

The HRD1-SEL1L ubiquitin ligase regulates stress granule homeostasis in couple with distinctive signaling branches of ER stress.

Wenbo Shi, Ran Ding, Yilin Chen, Fubo Ji, Junfang Ji, Weirui Ma, Jianping Jin.

Stress granules (SGs) are membrane-less cellular compartments which are dynamically assembled via biomolecular condensation mechanism when eukaryotic cells encounter environmental stresses. SGs are important for gene expression and cell fate regulation. Dysregulation of SG homeostasis has been linked to human neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we report that the HRD1-SEL1L ubiquitin ligase complex specifically regulates the homeostasis of heat shock-induced SGs through the ubiquitin-proteasome system (UPS) and the UPS-associated ATPase p97. Mechanistically, the HRD1-SEL1L complex mediates SG homeostasis through the BiP-coupled PERK-eIF2α signaling axis of endoplasmic reticulum (ER) stress, thereby coordinating the unfolded protein response (UPR) with SG dynamics. Furthermore, we show that the distinctive branches of ER stress play differential roles in SG homeostasis. Our study indicates that the UPS and the UPR together via the HRD1-SEL1L ubiquitin ligase to maintain SG homeostasis in a stressor-dependent manner.

Keywords: Cell biology; Cellular physiology; Functional aspects of cell biology

DOI: https://doi.org/10.1016/j.isci.2024.110196

Life Sci. 2024 Jul 04. pii: S0024-3205(24)00482-X. [Epub ahead of print] 122892

Endoplasmic reticulum stress as a target for retinoids in cancer treatment.

Anna Walczak-Szeffer, Agnieszka Wanda Piastowska-Ciesielska.

Retinoids, natural and synthetic derivatives of vitamin A, have various regulatory activities including controlling cellular proliferation, differentiation, and death. Furthermore, they have been used to treat specific cancers with satisfying results. Nevertheless, retinoids have yet to be converted into effective systemic therapies for the majority of tumor types. Regulation of unfolded protein response signaling, and persistent activation of endoplasmic reticulum stress (ER-stress) are promising treatment methods for cancer. The present article reviews the current understanding of how vitamin A and its derivatives may aid to cause ER-stress-activated apoptosis, as well as therapeutic options for exploiting ER-stress for achieving beneficial goal. The therapeutic use of some retinoids discussed in this article was related to decreased disease recurrence and improved therapeutic outcomes via ER-stress activation and promotion, indicating that retinoids may play an important role in cancer treatment and prevention. More research is needed to expand the use of vitamin A derivatives in cancer therapy, either alone or in combination with unfolded protein response inducers.

Keywords: Cancer; ER-stress; Retionoids; Unfolded protein response

DOI: https://doi.org/10.1016/j.lfs.2024.122892

Heliyon. 2024 Jun 30. 10(12): e32969

Hsa_circRNA_101036 aggravates hypoxic-induced endoplasmic reticulum stress via the miR-21-3p/TMTC1 axis in oral squamous cell carcinoma.

Wei Deng, Juan Fu, Shigeng Lin, Qitao Wen, Liangbin Fu, Xiaoze Chen.

Objective: Circular RNAs (circRNAs) have been identified as potential biomarkers and therapeutic targets for various types of cancer, including Oral squamous cell carcinoma (OSCC). Hsa_circRNA_101036 was found to function as a cancer suppressor gene in OSCC; however, the underlying regulatory mechanism remains unclear. We investigated the role of hsa_circRNA_101036 in OSCC development and progression and explored its potential as a therapeutic target.Methods: We performed a bioinformatics analysis and used experimental approaches to investigate the regulatory mechanism of hsa_circRNA_101036. The database StarBase v.2.0 was used to predict potential target-miRNAs of hsa_circRNA_101036. The levels of hsa_circRNA_101036, miR-21-3p, and TMTC2 expression in samples of OSCC cancer tissue (n = 15) and adjacent tissue (n = 15) were determined. We also examined the effects of hsa_circRNA_101036 overexpression on OSCC cell lines by using cell viability, migration, and invasion assays. The proportions of apoptotic cells and the reactive oxygen species (ROS) levels were analyzed by flow cytometry. We also investigated how hsa_circRNA_101036 overexpression affected the levels of miR-21-3p and TMTC2, and endoplasmic reticulum (ER) stress in OSCC cells.
Results: The levels of hsa_circRNA_101036 and TMTC2 expression were significantly lower, while miR-21-3p expression was higher in tumor tissues and OSCC cells when compared to adjacent tissues and normal oral fibroblasts, respectively. The levels of HIF-1α and miR-21-3p expression were significantly increased under conditions of hypoxia, while the levels of hsa_circRNA_101036 and TMTC2 were decreased. The expression levels of proteins associated with ER stress, the proportions of apoptotic cells, and the levels of ROS were all increased by hypoxia stimulation. In addition, overexpression of hsa_circRNA_101036, but not mutant hsa_circRNA_101036, was found to enhance the effect of hypoxia on HSC3 and OECM-1 cells. Hsa_circRNA_101036 overexpression suppressed tumor growth and induced ER stress. Finally, knockdown of miR-21-3p had the same effect as overexpression of hsa_circRNA_101036.
Conclusion: Our findings suggest that hsa_circRNA_101036 plays a critical role in the development and progression of OSCC. Overexpression of hsa_circRNA_101036 aggravated ER stress, and increased cell apoptosis and ROS production in OSCC under hypoxic conditions. Hsa_circRNA_101036 up-regulated TMTC2 expression by sponging miR-21-3p in OSCC.

Keywords: CircRNA; Endoplasmic reticulum stress; Oral squamous cell carcinoma; miR-21-3p

DOI: https://doi.org/10.1016/j.heliyon.2024.e32969

Biochem Biophys Res Commun. 2024 Jul 05. pii: S0006-291X(24)00901-X. [Epub ahead of print]730 150365

Reduced expression of NUPR1 alleviates epilepsy progression via attenuating ER stress.

Ying Cui, Guang Yang, Hong Li, Jianying Sun, Xiaoman Liu, Xiaohan Xia.

Epilepsy is a neurological disorder characterized by recurring seizures. It is necessary to further understand the mechanisms of epilepsy in order to develop novel strategies for its prevention and treatment. Abnormal endoplasmic reticulum stress (ERS) activation is related to the pathogenesis of epilepsy. Nuclear protein 1, transcriptional regulator (NUPR1) is involved in ERS and it might play a role in epilepsy progression. In the present study, we generated an epileptic mouse model using pilocarpine induction. After 72 h of pilocarpine treatment, the expression of NUPR1 was increased in epileptic mice. Furthermore, NUPR1 knockdown reduced the number of spontaneous recurrent seizures and alleviated hippocampal damage in these mice. Interestingly, NUPR1 knockdown also reduced the protein expression levels of LC3, PINK1, and Parkin in the mitochondria, and decreased the PINK1 expression in hippocampus. Additionally, the expression of ERS-related proteins-cleaved caspase-12, ATF4, and CHOP-decreased in epileptic mice following NUPR1 knockdown. In vitro experiments showed that the absence of NUPR1 reduced the expression of ATF4, CHOP, and cleaved caspase-12 in hippocampal neurons and inhibited the neuron apoptosis. In all, our study suggested that NUPR1 maybe a potential molecular target for epilepsy therapy.

Keywords: Endoplasmic reticulum stress; Epilepsy; Hippocampus; NUPR1

DOI: https://doi.org/10.1016/j.bbrc.2024.150365