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Activating ATF6 in spinal muscular atrophy promotes SMN expression and motor neuron survival through the IRE1α-XBP1 pathway.

AIM: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by survival of motor neuron (SMN) deficiency that induces motor neuron (MN) degeneration and severe muscular atrophy. Gene therapies that increase SMN have proven their efficacy but not for all patients. Here, we explored the unfolded protein response (UPR) status in SMA pathology and explored whether UPR modulation could be beneficial for SMA patients. METHODS: We analysed the expression and activation of key UPR proteins by RT-qPCR and by western blots in SMA patient iPSC-derived MNs and one SMA cell line in which SMN expr…

Atherogenic diets exacerbate colitis in mice deficient in glutathione peroxidase.

BACKGROUND: The proinflammatory effect of high-fat diet has been observed beyond the cardiovascular system, but there is little evidence to … ssion, plasma lipopolysaccharide, and TNF-α levels. The Chol+/CA diet lowered the expression of the unfolded protein response genes ATF6, CHOP, unspliced Xbp(U) , and Grp78/Bip, in WT and DKO mice compared with mice on the Chol- diet. CONCLUSIONS: We concluded that a cholesterol diet weakens the colon unfolded protein response, which can aggravate spontaneous colitis, lea …

Interdomain linkers tune the energy dissipation of immunoglobulin domains in titin.

Mechanical forces are central to biological function, with mechanosensitive multidomain proteins (MDPs) such as titin translating strain into adaptive responses. While damping is well recognized at the tissue level in muscles, how it emerges from a multidomain protein connected by interdomain linkers (IDLs) has remained unclear. Here, using magnetic tweezers, we probe engineered titin I27 dimers connected by three distinct synthetic linkers (RS, GG, and GGGSGGGG) under both equilibrium constant force clamp and far-from-equilibrium oscillatory force pulse protocols. We show that folded domains

Fava bean and pea protein hydrolysates modulate stress responses in C. elegans through different mechanisms.

The growing global demand for protein, combined with the urgent need for effective strategies to manage conditions such as obesity and diabe … gans, and gene expression and mutant analyses revealed the involvement of the endoplasmic reticulum unfolded protein response (ER-UPR) pathway in mediating its health-promoting effects. Together, our data demonstrate that fava bean and pea protein hydrolysates support healthspan in C. elegans by modulating distinct cellular stress response pathways and pave the way for fur …

CDS-localized m6A drives co-translational RNA decay to relieve biotic and abiotic endoplasmic reticulum stresses.

The endoplasmic reticulum (ER) mitigates stress typically through unfolded protein response (UPR) and ER-associated degradation (ERAD) pathways, yet post-transcriptional regulation of ER stress remains poorly defined. N6-methyladenosine (m6A) modification, predominantly enriched near stop codons, can govern mRNA fates via P-bodies or stress granules in stress conditions. m6A also occurs within coding sequences (CDS-m6A), but its role remains unappreciated in plants. Here we demonstrate that m6A ablation sensitizes Arabidopsis ER stress despite normal UPR and ERAD activities. Mechanistically, C…

Mitochondrial fission mediates an evolutionarily conserved antibacterial defense response.

Animals engage pleiotropic immune defense mechanisms to survive infections. Here, we present a function for mitochondrial fission in host defense. Challenge of macrophages with Escherichia coli increased mitochondrial fission, with this response promoting bacterial clearance in mammalian macrophages and Caenorhabditis elegans. E. coli-induced mitochondrial fission engaged dual antibacterial responses via the mitochondrial unfolded protein response (UPRmt) and inducible lipid droplet production. Mitochondrial fission-triggered UPRmt, characterized by activation of activating transcription facto…

Endoplasmic reticulum stress and steroidogenic dysfunction in Leydig cells: Molecular mechanisms of UPR-mediated testosterone regulation.

This review aims to synthesize current evidence on how endoplasmic reticulum (ER) stress affects steroidogenic function in Leydig cells. It explores the mechanisms by which ER stress activates the unfolded protein response (UPR) and autophagy pathways, ultimately influencing testosterone production and cellular homeostasis. The central research question addresses how ER stress-induced signaling modulates the transcriptional regulation of key steroidogenic enzymes and contributes to age-related declines in androgen synthesis. A comprehensive literature review was conducted using recent findings…

Endoplasmic reticulum stress in liver fibrosis: Mechanisms and therapeutic potential.

This paper reviews the important role of endoplasmic reticulum stress in the patho mechanism of liver fibrosis and its potential as a potent … ic liver disease, including alcohol-related liver disease, viral hepatitis, and liver fibrosis. The unfolded protein response is one of the important response mechanisms to endoplasmic reticulum stress. It is associated with several pathological aspects of liver fibrosis and the maintenance of endoplasmic reticulum homeostasis. Interventions targeting endoplasmic reticulum …

Молекулярное взаимодействие между окислительным и эндоплазмическим ретикулумным стрессом при множественном склерозе.

Множественный склероз (MS) — изнурительное неврологическое состояние, вызванное повреждением центральной нервной системы (КНС) при иммунизированном воздействии, приводящее к разрушению миэлина и постепенному нарушению волокна нервной системы. В недавних исследованиях в качестве основных факторов, способствующих патологии MS, были определены окислительный стресс и эндоплазмический ретикулум (ER). Когда противоокислительная защита не позволяет нейтрализовать чрезмерные химически активные виды кислорода (РОС), происходит окислительное повреждение, причиняющее вред липидам, белкам и ДНК внутри ней

Совпадение в аннотации оригинала
Multiple sclerosis (MS) is a debilitating neurological condition driven by immune-mediated damage to the central nervous system (CNS), leadi … ER stress emerges when misfolded proteins overload the organelle's folding capacity, prompting the unfolded protein response (UPR) to mitigate the crisis. However, prolonged ER stress can shift cellular signaling toward apoptosis, particularly damaging oligodendrocytes and axons in MS. A critical bidirectional relationship exists between these stress pathways-oxidative di …

Regulation of chondrocyte apoptosis in osteoarthritis by endoplasmic reticulum stress.

Osteoarthritis (OA), a common degenerative joint disease, is characterized by the apoptosis of chondrocytes as a primary pathophysiological change, with endoplasmic reticulum stress (ERS) playing a crucial role. It has been demonstrated that an imbalance in endoplasmic reticulum (ER) homeostasis can lead to ERS, activating three cellular adaptive response pathways through the unfolded protein response to restore ER homeostasis. Mild ERS exerts a protective effect on cells, while prolonged ERS that disrupts the self-regulatory balance of the ER activates apoptotic signaling pathways, leading to…

Chaperone-Dependent Mechanisms as a Pharmacological Target for Neuroprotection.

Modern pharmacotherapy of neurodegenerative diseases is predominantly symptomatic and does not allow vicious circles causing disease develop … he aim of this review was to analyze the mechanisms of endoplasmic reticulum stress (ER stress) and unfolded protein response (UPR) in the pathogenesis of neurodegenerative diseases. Data on BiP and Sigma1R chaperones in clinical and experimental studies of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are presented. The …

The endoplasmic reticulum: Homeostasis and crosstalk in retinal health and disease.

The endoplasmic reticulum (ER) is the largest intracellular organelle carrying out a broad range of important cellular functions including p … ion of cells. This vital process is implemented through well-orchestrated signaling pathways of the unfolded protein response (UPR). The UPR is activated when misfolded or unfolded proteins accumulate in the ER, a condition known as ER stress, and functions to restore ER homeostasis thus promoting cell survival. However, prolonged activation or dysregulation of the UPR can …

Dysregulated UPR and ER Stress Related to a Mutation in the Sdf2l1 Gene Are Involved in the Pathophysiology of Diet-Induced Diabetes in the Cohen Diabetic Rat.

The Cohen Diabetic rat is a model of type 2 diabetes mellitus that consists of the susceptible (CDs/y) and resistant (CDr/y) strains. Diabetes develops in CDs/y provided diabetogenic diet (DD) but not when fed regular diet (RD) nor in CDr/y given either diet. We recently identified in CDs/y a deletion in Sdf2l1, a gene that has been attributed a role in the unfolded protein response (UPR) and in the prevention of endoplasmic reticulum (ER) stress. We hypothesized that this deletion prevents expression of SDF2L1 and contributes to the pathophysiology of diabetes in CDs/y by impairing UPR, enhan…

Noncanonical Form of ERAD Regulates Cardiac Hypertrophy.

BACKGROUND: Cardiac hypertrophy increases demands on protein folding, which causes an accumulation of misfolded proteins in the endoplasmic reticulum (ER). These misfolded proteins can be removed by the adaptive retrotranslocation, polyubiquitylation, and a proteasome-mediated degradation process, ER-associated degradation (ERAD), which, as a biological process and rate, has not been studied in vivo. To investigate a role for ERAD in a pathophysiological model, we examined the function of the functional initiator of ERAD, valosin-containing protein-interacting membrane protein (VIMP), positing

Proteostasis in Parkinson's disease: Recent development and possible implication in diagnosis and therapeutics.

The protein dyshomeostasis is identified as the hallmark of many age-related neurodegenerative disorders including Parkinson's disease (PD). The diseased brain shows the deposition of Lewy bodies composed of α-synuclein protein aggregates. Functional proteostasis is characterized by the well-coordinated signaling network constituting unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and the autophagy-lysosome pathway (ALP). These networks ensure proper synthesis, folding, confirmation, and degradation of protein i.e., α-synuclein protein in PD. The proper functioning the …

Functional and morphological impact of ER stress on mitochondria.

Over the past years, knowledge and evidence about the existence of crosstalks between cellular organelles and their potential effects on survival or cell death have been constantly growing. More recently, evidence accumulated showing an intimate relationship between endoplasmic reticulum (ER) and mitochondria. These close contacts not only establish extensive physical links allowing exchange of lipids and calcium but they can also coordinate pathways involved in cell life and death. It is now obvious that ER dysfunction/stress and unfolded protein response (UPR) as well as mitochondria play ma…

A reporter for tracking the UPR in vivo reveals patterns of temporal and cellular stress during atherosclerotic progression.

Progression of human arteriosclerosis is associated with and promoted by induction of the endoplasmic reticulum (ER) stress pathway known as the unfolded protein response (UPR). Most studies that assess UPR markers in atherosclerosis rely on methodologies that suffer from low signal sensitivity, nonspecific immunohistochemistry, or inability to resolve differences between cellular subsets. To accurately monitor the UPR independently of artifacts generated postmortem, we describe here the first in vivo reporter for ER stress during atherosclerosis. Mice transgenic for the fluorescent XBP-1 ER s…

Improper protein trafficking contributes to artemisinin sensitivity in cells lacking the KDAC Rpd3p.

Lysine deacetylases (KDACs) inhibitors may have therapeutic value in anti-malarial combination therapies with artemisinin. To evaluate connections between KDACs and artemisinin, Saccharomyces cerevisiae deletion mutants in KDAC genes were assayed. Deletion of RPD3, but not other KDAC genes, resulted in strong sensitivity to artemisinin, which was also observed in sit4Δ mutants with impaired endoplasmic reticulum (ER) to Golgi protein trafficking. Decreased accumulation of the transporters Pdr5p, Fur4p, and Tat2p was observed in rpd3Δ and sit4Δ cells. The unfolded protein response is induced in…

Unfolding transitions of Bacillus anthracis protective antigen.

Protective antigen (PA) is an 83kDa protein which, although essential for toxicity of Bacillus anthracis, is harmless and an effective vaccine component. In vivo it undergoes receptor binding, proteolysis, heptamerisation and membrane insertion. Here we probe the response of PA to denaturants, temperature and pH. We present analyses (including barycentric mean) of the unfolding and refolding behavior of PA and reveal the origin of two critical steps in the denaturant unfolding pathway in which the first step is a calcium and pH dependent rearrangement of domain 1. Thermal unfolding fits a sing

GRP78 Selective Inhibitors From a Direct-to-Biology Strategy.

Because cancer cells have heightened protein homeostasis (proteostasis) requirements, there is interest in targeting proteostasis machinery, … tral component of protein homeostasis in the secretory system and is the principal regulator of the unfolded protein response (UPR). Here, we report the use of a direct-to-biology (D2B) strategy to optimize a dipeptide-based scaffold that binds selectively to GRP78, relative to the other canonical HSP70s. We show that our lead compound, 12, potently and selectively inhibit …