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OBJECTIVE: The mitochondrial unfolded protein response (UPRmt) is an adaptive cellular response to stress to ensure mitochondrial proteostasis and function. Here we explore the capacity of physical exercise to induce UPRmt in the skeletal muscle. METHODS: Therefore, we combined mouse models of exercise (swimming and treadmill running), pharmacological intervention, and bioinformatics analyses. RESULTS: Firstly, RNA sequencing and Western blotting analysis revealed that an acute aerobic session stimulated several mitostress-related genes and protein content in muscle, including the UPRmt markers. Conversely, using a large panel of isogenic strains of BXD mice, we identified that BXD73a and 73b strains displayed low levels of several UPRmt-related genes in the skeletal muscle, and this genotypic feature was accompanied by body weight gain, lower locomotor activity, and aerobic capacity. Finally, we identified that c-Jun N-terminal kinase (JNK) activation was critical in exercise-induced UPRmt in the skeletal muscle since pharmacological JNK pathway inhibition blunted exercise-induced UPRmt markers in mice muscle. CONCLUSION: Our findings provide new insights into how exercise triggers mitostress signals toward the oxidative capacity in the skeletal muscle.

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Fungi are a diverse group of eukaryotic organisms that infect humans, animals, and plants. To successfully colonize their hosts, pathogenic fungi must continuously adapt to the host's unique environment, e.g., changes in temperature, pH, and nutrient availability. Appropriate protein folding, assembly, and degradation are essential for maintaining cellular homeostasis and survival under stressful conditions. Therefore, the regulation of proteostasis is crucial for fungal pathogenesis. The heat shock response (HSR) is one of the most important cellular mechanisms for maintaining proteostasis. It is activated by various stresses and regulates the activity of heat shock proteins (HSPs). As molecular chaperones, HSPs participate in the proteostatic network to control cellular protein levels by affecting their conformation, location, and degradation. In recent years, a growing body of evidence has highlighted the crucial yet understudied role of stress response circuits in fungal infections. This review explores the role of protein homeostasis and HSPs in fungal pathogenicity, including their contributions to virulence and host-pathogen interactions, as well as the concerted effects between HSPs and the main proteostasis circuits in the cell. Furthermore, we discuss perspectives in the field and the potential for targeting the components of these circuits to develop novel antifungal therapies.

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Cardiovascular and renal diseases are among the leading causes of death worldwide, and regardless of current efforts, there is a demanding need for therapeutic alternatives to reduce their progression to advanced stages. The stress caused by diseases leads to the activation of protective mechanisms in the cell, including chaperone proteins. The Sigma-1 receptor (Sig-1R) is a ligand-operated chaperone protein that modulates signal transduction during cellular stress processes. Sig-1R interacts with various ligands and proteins to elicit distinct cellular responses, thus, making it a potential target for pharmacological modulation. Furthermore, Sig-1R ligands activate signaling pathways that promote cardioprotection, ameliorate ischemic injury, and drive myofibroblast activation and fibrosis. The role of Sig-1R in diseases has also made it a point of interest in developing clinical trials for pain, neurodegeneration, ischemic stroke, depression in patients with heart failure, and COVID-19. Sig-1R ligands in preclinical models have significantly beneficial effects associated with improved cardiac function, ventricular remodeling, hypertrophy reduction, and, in the kidney, reduced ischemic damage. These basic discoveries could inform clinical trials for heart failure (HF), myocardial hypertrophy, acute kidney injury (AKI), and chronic kidney disease (CKD). Here, we review Sig-1R signaling pathways and the evidence of Sig-1R modulation in preclinical cardiac and renal injury models to support the potential therapeutic use of Sig-1R agonists and antagonists in these diseases.

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The endoplasmic reticulum (ER) is a complex multifunctional organelle that maintains cell homeostasis. Intrinsic and extrinsic factors alter ER functions, including the rate of protein folding that triggers the accumulation of misfolded proteins and alters homeostasis, thus generating stress in the ER, which activates the unfolded protein response (UPR) pathway to promote cell survival and restore their homeostasis; however, if the damage is not corrected, it could also trigger cell death. In addition, ER stress and oxidative stress are closely related because excessive production of reactive oxygen species (ROS), a well-known inducer of ER stress, promotes the accumulation of misfolded proteins; at the same time, the ER stress enhances ROS production, generating a pathological cycle. Furthermore, it has been described that the dysregulation of the UPR contributes to the progression of various diseases, so the use of compounds capable of regulating ER stress, such as antioxidants, has been used in several experimental models of diseases to alleviate the damage induced by the maladaptive signaling of the UPR, the mechanism of action of antioxidants generally is dose-dependent, and it is specific in each tissue and pathology, could decrease or enhance specific proteins of the UPR to have beneficial or detrimental effects.

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Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

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PURPOSE: The aberrant mRNA expression of a UPR component Cation transport regulator homolog 1 (CHAC1) has been reported to be associated with poor survival in breast and ovarian cancer patients, however, the expression of CHAC1 at protein levels in malignant breast tissues is underreported. The following study aimed at analyzing CHAC1 protein expression in malignant breast cancer tissues. METHODS: Evaluation of CHAC1 expression in invasive ductal carcinomas (IDCs) with known ER, PR, and HER2 status was carried out using immunohistochemistry (IHC) with CHAC1 specific antibody. The Human breast cancer tissue microarray (TMA, cat# BR1503f, US Biomax, Inc., Rockville, MD) was used to determine CHAC1 expression. The analysis of CHAC1 IHC was done to determine its expression in terms of molecular subtypes of breast cancer, lymph node status, and proliferation index using Qu-Path software. Survival analysis was studied with a Kaplan-Meier plotter. RESULTS: Immunohistochemical analysis of CHAC1 in breast cancer tissues showed significant up-regulation of CHAC1 as compared to the adjacent normal and benign tissues. Interestingly, CHAC1 immunostaining revealed high expression in tumor tissues with high proliferation and positive lymph node metastasis suggesting that CHAC1 might have an important role to play in breast cancer progression. Furthermore, high CHAC1 expression is associated with poor overall survival (OS) in large breast cancer patient cohorts. CONCLUSION: As a higher expression of CHAC1 was observed in tissue cores with high Ki67 index and positive lymph node metastasis it may be concluded that enhanced CHAC1 expression correlates with proliferation and metastasis. The further analysis of breast cancer patients' survival data through KM plot indicated that high CHAC1 expression is associated with a bad prognosis hinting that CHAC1 may have a possible prognostic significance in breast cancer.

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We are living in a terrifying pandemic caused by Sars-CoV-2, in which patients with diabetes mellitus have, from the beginning, been identified as having a high risk of hospitalization and mortality. This viral disease is not limited to the respiratory system, but also affects, among other organs, the central nervous system. Furthermore, we already know that individuals with diabetes mellitus exhibit signs of astrocyte dysfunction and are more likely to develop cognitive deficits and even dementia. It is now being realized that COVID-19 incurs long-term effects and that those infected can develop several neurological and psychiatric manifestations. As this virus seriously compromises cell metabolism by triggering several mechanisms leading to the unfolded protein response (UPR), which involves endoplasmic reticulum Ca2+ depletion, we review here the basis involved in this response that are intimately associated with the development of neurodegenerative diseases. The discussion aims to highlight two aspects-the role of calcium-binding proteins and the role of astrocytes, glial cells that integrate energy metabolism with neurotransmission and with neuroinflammation. Among the proteins discussed are calpain, calcineurin, and sorcin. These proteins are emphasized as markers of the UPR and are potential therapeutic targets. Finally, we discuss the role of drugs widely prescribed to patients with diabetes mellitus, such as statins, metformin, and calcium channel blockers. The review assesses potential neuroprotection mechanisms, focusing on the UPR and the restoration of reticular Ca2+ homeostasis, based on both clinical and experimental data.

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In addition to the UPR pathway, yeast cells require components of the HOG pathway to respond to ER stress. In this work, we found that unphosphorylated Sln1 and Ssk1 are required to mount an appropriate response to Tn. We also found that the MAPKKKs Ssk2 participates in the Tn response, but its osmo-redundant protein Ssk22 does not. We also found that the Pbs2 docking sites for Ssk2 (RDS-I and KD) are partially dispensable when mutated separately; however, the prevention of Ssk2 binding to Pbs2, by the simultaneous mutation of RDS-I and KD, caused strong sensitivity to Tn. In agreement with the lack of Hog1 phosphorylation during Tn treatment, a moderate resistance to Tn is obtained when a Pbs2 version lacking its kinase activity is expressed; however, the presence of mutual Pbs2-Hog1 docking sites is essential for the Tn response. Finally, we detected that Tn induced a transcriptional activation of some components of the SLN1 branch. These results indicate that the Tn response requires a complex formed by the MAPK module and components of the SLN1 branch but not their canonical osmoregulatory activities.

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The intracellular mechanisms safeguarding DC function are of biomedical interest in several immune-related diseases. Type 1 conventional DCs (cDC1s) are prominent targets of immunotherapy typified by constitutive activation of the unfolded protein response (UPR) sensor IRE1. Through its RNase domain, IRE1 regulates key processes in cDC1s including survival, ER architecture and function. However, most evidence linking IRE1 RNase with cDC1 biology emerges from mouse studies and it is currently unknown whether human cDC1s also activate the enzyme to preserve cellular homeostasis. In this work, we report that human cDC1s constitutively activate IRE1 RNase in steady state, which is evidenced by marked expression of IRE1, XBP1s, and target genes, and low levels of mRNA substrates of the IRE1 RNase domain. On a functional level, pharmacological inhibition of the IRE1 RNase domain curtailed IL-12 and TNF production by cDC1s upon stimulation with TLR agonists. Altogether, this work demonstrates that activation of the IRE1/XBP1s axis is a conserved feature of cDC1s across species and suggests that the UPR sensor may also play a relevant role in the biology of the human lineage.

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The unfolded protein response (UPR) is a complex network of intracellular pathways that transmits signals from ER lumen and/or ER bilayer to the nuclear compartment in order to activate gene transcription. UPR is activated by the loss of ER capacities, known as ER stress, and occurs to restore ER properties. In this regard, glycerolipid (GL) synthesis activation contributes to ER membrane homeostasis and IRE1α-XBP1, one UPR pathway, has a main role in lipogenic genes transcription. Herein, we describe the strategy and methodology used to evaluate whether IRE1α-XBP1 pathway regulates lipid metabolism in renal epithelial cells subjected to hyperosmolar environment. XBP1s activity was hindered by blocking IRE1α RNAse activity and by impeding its expression; under these conditions, we determined GL synthesis and lipogenic enzymes expression.

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