bims-ershed 2023-05-07 papers

bioRxiv. 2023 Apr 20. pii: 2023.04.19.537391. [Epub ahead of print]

Increased activity of IRE1 improves the clinical presentation of EAE.

Valerie Bracchi-Ricard, Kayla Nguyen, Daniela Ricci, Brian Gaudette, Jorge Henao-Meija, Roberta Brambilla, Tetyana Martynyuk, Tali Gidalevitz, David Allman, John R Bethea, Yair Argon.

Activation of the ER stress sensor IRE1α contributes to neuronal development and is known to induce neuronal remodeling in vitro and in vivo . On the other hand, excessive IRE1 activity is often detrimental and may contribute to neurodegeneration. To determine the consequences of increased activation of IRE1α, we used a mouse model expressing a C148S variant of IRE1α with increased and sustained activation. Surprisingly, the mutation did not affect the differentiation of highly secretory antibody-producing cells, but exhibited a strong protective effect in a mouse model of experimental autoimmune encephalomyelitis (EAE). Significant improvement in motor function was found in IRE1C148S mice with EAE relative to WT mice. Coincident with this improvement, there was reduced microgliosis in the spinal cord of IRE1C148S mice, with reduced expression of pro-inflammatory cytokine genes. This was accompanied by reduced axonal degeneration and enhanced CNPase levels, suggestiing improved myelin integrity. Interestingly, while the IRE1C148S mutation is expressed in all cells, the reduction in proinflammatory cytokines and in the activation of microglial activation marker IBA1, along with preservation of phagocytic gene expression, all point to microglia as the cell type contributing to the clinical improvement in IRE1C148S animals. Our data suggest that sustained increase in IRE1α activity can be protective in vivo , and that this protection is cell type and context dependent. Considering the overwhelming but conflicting evidence for the role of the ER stress in neurological diseases, a better understanding of the function of ER stress sensors in physiological contexts is clearly needed.

DOI: https://doi.org/10.1101/2023.04.19.537391

DNA Cell Biol. 2023 May 03.

Endoplasmic Reticulum Stress: A Key Regulator of Cardiovascular Disease.

Zhao Chen, Shi-Liang Zhang.

The problems associated with economic development and social progress have led to an increase in the occurrence of cardiovascular diseases (CVDs), which affect the health of an increasing number of people and are a leading cause of disease and population mortality worldwide. Endoplasmic reticulum stress (ERS), a hot topic of interest for scholars in recent years, has been confirmed in numerous studies to be an important pathogenetic basis for many metabolic diseases and play an important role in maintaining physiological processes. The endoplasmic reticulum (ER) is a major organelle that is involved in protein folding and modification synthesis, and ERS occurs when several physiological and pathological factors allow excessive amounts of unfolded/misfolded proteins to accumulate. ERS often leads to initiation of the unfolded protein response (UPR) in a bid to re-establish tissue homeostasis; however, UPR has been documented to induce vascular remodeling and cardiomyocyte damage under various pathological conditions, leading to or accelerating the development of CVDs such as hypertension, atherosclerosis, and heart failure. In this review, we summarize the latest knowledge gained concerning ERS in terms of cardiovascular system pathophysiology, and discuss the feasibility of targeting ERS as a novel therapeutic target for the treatment of CVDs. Investigation of ERS has immense potential as a new direction for future research involving lifestyle intervention, the use of existing drugs, and the development of novel drugs that target and inhibit ERS.

Keywords: arrhythmia; atherosclerosis; endoplasmic reticulum stress; hypertension; ischemic cardiomyopathy; unfolded protein response

DOI: https://doi.org/10.1089/dna.2022.0532

Pharmacol Rev. 2023 May 01. pii: PHARMREV-AR-2022-000701. [Epub ahead of print]

Pharmacological regulation of endoplasmic reticulum structure and calcium dynamics: importance for neurodegenerative diseases.

Ilmari Parkkinen, Anna Their, Muhammad Yasir Asghar, Sreesha Sree, Eija Jokitalo, Mikko Airavaara.

The endoplasmic reticulum (ER) is the largest organelle of the cell, composed of a continuous network of sheets and tubules, and is involved in protein, calcium (Ca2+) and lipid homeostasis. In neurons, the ER extends throughout the cell, both somal and axodendritic compartments, and is highly important for neuronal functions. A third of the proteome of a cell, secreted and membrane-bound proteins, are processed within the ER lumen and most of these proteins are vital for neuronal activity. The brain itself is high in lipid content and many structural lipids are produced, in part, by the ER. Cholesterol and steroid synthesis are strictly regulated in the ER of the blood-brain barrier protected brain cells. The high Ca2+ level in the ER lumen and low cytosolic concentration is needed for Ca2+-based intracellular signaling, also for synaptic signaling and Ca2+ waves, as well as preparing proteins for correct folding in the presence of high Ca2+ concentrations to cope with the high concentrations of extracellular milieu. Particularly, ER Ca2+ is controlled in axodendritic areas for proper neurito- and synaptogenesis and synaptic plasticity and remodeling. In this review, we cover the physiological functions of the neuronal ER and discuss it in context of common neurodegenerative diseases focusing on pharmacological regulation of ER Ca2+ Furthermore, we postulate that heterogeneity of the ER, its protein folding capacity and ensuring Ca2+ regulation is a crucial factor for the aging and selective vulnerability of neurons in various neurodegenerative diseases. Significance Statement ER Ca2+ regulators are promising therapeutic targets for degenerative diseases for which efficacious drug therapies do not exist. The use of pharmacological probes targeting maintenance and restoration of ER Ca2+ can provide restoration of protein homeostasis, e.g. folding of complex plasma membrane signalling receptors and slow down the degeneration process of neurons.

Keywords: Alzheimer's Disease; Endoplasmic reticulum stress; Parkinson's Disease; calcium; endoplasmic reticulum; endorphin; neurodegeneration

DOI: https://doi.org/10.1124/pharmrev.122.000701

Nat Rev Cancer. 2023 May 04.

The role of eIF4F-driven mRNA translation in regulating the tumour microenvironment.

Margarita Bartish, Madelyn J Abraham, Christophe Gonçalves, Ola Larsson, Charlotte Rolny, Sonia V Del Rincón.

Cells can rapidly adjust their proteomes in dynamic environments by regulating mRNA translation. There is mounting evidence that dysregulation of mRNA translation supports the survival and adaptation of cancer cells, which has stimulated clinical interest in targeting elements of the translation machinery and, in particular, components of the eukaryotic initiation factor 4F (eIF4F) complex such as eIF4E. However, the effect of targeting mRNA translation on infiltrating immune cells and stromal cells in the tumour microenvironment (TME) has, until recently, remained unexplored. In this Perspective article, we discuss how eIF4F-sensitive mRNA translation controls the phenotypes of key non-transformed cells in the TME, with an emphasis on the underlying therapeutic implications of targeting eIF4F in cancer. As eIF4F-targeting agents are in clinical trials, we propose that a broader understanding of their effect on gene expression in the TME will reveal unappreciated therapeutic vulnerabilities that could be used to improve the efficacy of existing cancer therapies.

DOI: https://doi.org/10.1038/s41568-023-00567-5