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Understanding ER homeostasis and the UPR to enhance treatment efficacy of acute myeloid leukemia.

Protein biogenesis, maturation and degradation are tightly regulated processes that are governed by a complex network of signaling pathways. The endoplasmic reticulum (ER) is responsible for biosynthesis and maturation of secretory proteins. Circumstances that alter cellular protein homeostasis, determine accumulation of misfolded and unfolded proteins in the ER, a condition defined as ER stress. In case of stress, the ER activates an adaptive response called unfolded protein response (UPR), a series of pathways of major relevance for cancer biology. The UPR plays a preeminent role in adaptati…

Endoplasmic Reticulum Stress: Implications in Diseases.

Endoplasmic reticulum (ER) is a specialized organelle that plays a significant role in cellular function. The major functions of ER include protein synthesis and transport, folding of proteins, biosynthesis of lipids, calcium (Ca2+) storage, and redox balance. The loss of ER integrity results in the induction of ER stress within the cell due to the accumulation of unfolded, improperly folded proteins or changes in Ca2+ metabolism and redox balance of organelle. This ER stress commences the Unfolded Protein Response (UPR) that serves to counteract the ER stress via three sensors inositol requir…

Unravelling the Complex Denaturant and Thermal-Induced Unfolding Equilibria of Human Phenylalanine Hydroxylase.

Human phenylalanine hydroxylase (PAH) is a metabolic enzyme involved in the catabolism of L-Phe in liver. Loss of conformational stability and decreased enzymatic activity in PAH variants result in the autosomal recessive disorder phenylketonuria (PKU), characterized by developmental and psychological problems if not treated early. One current therapeutic approach to treat PKU is based on pharmacological chaperones (PCs), small molecules that can displace the folding equilibrium of unstable PAH variants toward the native state, thereby rescuing the physiological function of the enzyme. Underst

Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers.

Infections with Salmonella enterica serovars Typhi and Paratyphi A cause an estimated 14 million cases of enteric fever annually. Here, the … e most strongly associated with enteric fever susceptibility (P = 0.011). Gene sets relating to the unfolded protein response/heat shock and endoplasmic reticulum-associated protein degradation were overrepresented in HLA-B*27:05+ participants following challenge. Furthermore, intracellular replication of S. Typhi is higher in C1R cells transfected with HLA-B*27:05 (P = 0. …

Redox-Encoded Proteostasis: Heat Shock Proteins as Integrators of Stress Adaptation and Therapeutic Targets.

SIGNIFICANCE: Cellular proteostasis is essential for cellular proteome integrity, which is exquisitely sensitive to the redox environment. H … ctions, HSPs also play critical roles in organelle-specific stress responses, such as mitochondrial unfolded protein response, endoplasmic reticulum (ER) stress, and unfolded protein response. CRITICAL ISSUES: Despite the well-known contributions of HSPs to redox-proteostasis, the double-edged functions of HSPs in protein aggregation diseases remain unclear. The main issu …

Insights into the factors contributing to artemisinin resistance in Plasmodium falciparum.

Artemisinin (ART)-based combination therapies are instrumental in reducing the burden of malaria worldwide. However, the emergence of ART re … ding reduced haemoglobin endocytosis, increased phosphatidylinositol-3-kinase levels, activation of unfolded protein response and polymorphism in various other genes, also contribute to the development of resistance. This narrative provides an overview of the molecular mechanisms related to ARTR.

Identification and functional coordination analysis of gene co-expression networks in different tissues of XBP1 cartilage-specific deficient mice.

Abnormal differentiation and proliferation of chondrocytes leads to various diseases related to growth and development. The process of chondrocyte differentiation involves a series of complex cellular and molecular interactions. X-box binding protein 1 (XBP1), an essential molecule of the unfolded protein response (UPR) in Endoplasmic Reticulum (ER) stress, participated in cartilage development and causes other related diseases. We previously reported that XBP1 deficiency in cartilage impacts the function and associated diseases of many different tissues including cartilage. However, how diffe…

Inositol-requiring enzyme-1 regulates phosphoinositide signaling lipids and macrophage growth.

The ER-bound kinase/endoribonuclease (RNase), inositol-requiring enzyme-1 (IRE1), regulates the phylogenetically most conserved arm of the unfolded protein response (UPR). However, the complex biology and pathology regulated by mammalian IRE1 cannot be fully explained by IRE1's one known, specific RNA target, X box-binding protein-1 (XBP1) or the RNA substrates of IRE1-dependent RNA degradation (RIDD) activity. Investigating other specific substrates of IRE1 kinase and RNase activities may illuminate how it performs these diverse functions in mammalian cells. We report that macrophage IRE1 pla…

The Hsp90 inhibitor IPI-504 overcomes bortezomib resistance in mantle cell lymphoma in vitro and in vivo by down-regulation of the prosurvival ER chaperone BiP/Grp78.

Despite the promising introduction of the proteasome inhibitor bortezomib in the treatment of mantle cell lymphoma (MCL), not all patients r … ion provoked the dissociation of Hsp90/BiP complexes, leading to BiP/Grp78 depletion, inhibition of unfolded protein response, and promotion of NOXA-mediated mitochondrial depolarization. The IPI-504-bortezomib combination also prevented BiP/Grp78 accumulation, thereby promoting apoptosis and inhibiting the growth of bortezomib-resistant tumors in a mouse model of MCL xeno …

Crosstalk between advanced glycation and endoplasmic reticulum stress: emerging therapeutic targeting for metabolic diseases.

CONTEXT: Advanced glycation, the major posttranslational modification of proteins, DNA, and lipids, is accelerated under conditions of incre … glycation, can also adversely affect ER function, leading to pathogenic ER stress, followed by the unfolded protein response. The concomitant presence of advanced glycation in the same conditions with ER stress suggests their crosstalk in the progression of diseases associated with hypoxic and oxidative stress. CONCLUSION: Current data support the direct or indirect indu …

A novel signal transduction pathway from the endoplasmic reticulum to the nucleus is mediated by transcription factor NF-kappa B.

The inducible, higher eukaryotic transcription factor NF-kappa B is activated by a variety of external stimuli including inflammatory cytokines, viral and bacterial infection and UV irradiation. Here we show that internal stress, caused by the accumulation of proteins in the endoplasmic reticulum (ER), also induces NF-kappa B DNA binding as well as kappa B-dependent gene expression. This was observed upon expression of immunoglobulin mu chains in the absence of light chains and by treatment of cells with several agents known to cause ER stress, such as tunicamycin, brefeldin A, 2-deoxyglucose

Determination of the protective effects of boric acid against experimentally induced cholestasis with ANIT in rats.

Cholestasis is self-perpetuating: failure of canalicular bile salt export expands the intracellular bile acid pool, and retained acids progr … ctor 2α (eIF2α)-activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP) arm of the unfolded protein response (UPR) limit the downstream consequences. Forty male Sprague Dawley rats received vehicle, ANIT (50 mg/kg, intragastrically), boric acid (100 mg/kg/day, 7 days) before ANIT, or boric acid alone, and were sacrificed 24 h later. Transporters and the nu …

The emerging role of fat-inducing transcript 2 in endoplasmic reticulum proteostasis and lipoprotein biogenesis.

PURPOSE OF REVIEW: This review examines the evolving role of the fat-inducing transcript 2 (FIT2) protein in lipid droplet (LD) biology and … ith the ER-associated degradation (ERAD), is critical for protein homeostasis, and is linked to the unfolded protein response (UPR). Dysregulation of FIT2 has also been linked to metabolic disorders such as insulin resistance and lipodystrophy, highlighting its clinical relevance. SUMMARY: Insights into FIT2 function underscore its pivotal role in LD formation and lipid h …

Evidence From Human Placenta, Endoplasmic Reticulum-Stressed Trophoblasts, and Transgenic Mice Links Transthyretin Proteinopathy to Preeclampsia.

BACKGROUND: We have demonstrated that protein aggregation plays a pivotal role in the pathophysiology of preeclampsia and identified several … 1α (inositol-requiring enzyme-1α), PDI (protein disulfide isomerase), and Ero-1, all markers of the unfolded protein response, and the apoptosis mediator caspase-3. Blockade of IRE1α inhibited hypoxia/reoxygenation-induced upregulation of Ero-1 in PHTs. Excessive unfolded protein response activation was observed in the early-onset preeclampsia placenta. Importantly, pregna …

A Unique Pathogenic Heterozygous Hypoxia Up-Regulated Protein 1 (HYOU1) Mutation Presenting With Recurrent Osteomyelitis, Subglottic Stenosis, and Hypoglycemia.

The hypoxia up-regulated protein 1 (HYOU1) gene encodes a chaperone protein involved in maintaining cellular homeostasis by reducing oxidative stress and supporting the unfolded protein response in the endoplasmic reticulum and mitochondria. While homozygous HYOU1 mutations have been previously reported in patients with profound immunodeficiency, pancytopenia, and hypoglycemia, the clinical implications of heterozygous mutations remain less defined. We describe a patient with a heterozygous pathogenic HYOU1 mutation who presents with a longstanding history of recurrent infections, medically tr…

Индейка B Клеточный транскриптомный профиль во время турецкого геморрагического вируса энтерита (THEV)

Инфекция геморрагическим энтеритом индейки (THEV) может вызвать геморрагический энтерит, от которого страдают молодые индейки. Эта болезнь характеризуется кровопролитным диареей и иммунодепрессией (ИМС), что объясняется апоптозом инфицированных клеток B. Вторичные инфекции, вызванные МСМ, усугубляют экономические потери. Мы провели первый транскриптивный анализ инфекции ТЭВ, чтобы прояснить механизмы, с помощью которых происходит спровоцированная ТЭВ МСМ. После заражения и секвенирования mRNAs линии индейки B-клеток были нанесены скрипты генома индейки, а выражение гена было определено с помощ

Совпадение в аннотации оригинала
Infection with the turkey hemorrhagic enteritis virus (THEV) can cause hemorrhagic enteritis, which affects young turkeys. This disease is c … 4 hpi, respectively. The DEGs correlated with multiple biological processes including apoptosis, ER unfolded protein response, and cell maintenance. Multiple pro-apoptotic genes, including APAF1, BMF, BAK1, and FAS were upregulated. Genes that play a role in ER stress-induced unfolded protein response including VCP, UFD1, EDEM1, and ATF4 were also upregulated and may contr …

Differences in Mitochondrial Coupling Reveal a Novel Signature of Mitohormesis in Muscle of Healthy Individuals.

CONTEXT: Reduced mitochondrial coupling (ATP/O2 [P/O]) is associated with sedentariness and insulin resistance. Interpreting the physiologic … led group. A trend for higher mitonuclear protein imbalance (P = .06) and an elevated mitochondrial unfolded protein response (heat shock protein 60 protein; P = .004) were also identified in the coupled group. CONCLUSIONS: Higher muscle mitochondrial coupling is accompanied by an overall elevation in mitochondrial function, a novel transcriptional signature of oxidative …

Endoplasmic Reticulum Stress in Acute Myeloid Leukemia: Pathogenesis, Prognostic Implications, and Therapeutic Strategies.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy that poses a significant therapeutic challenge due to its high recurrence rate and demanding treatment regimens. Increasing evidence suggests that endoplasmic reticulum (ER) stress and downstream activation of the unfolded protein response (UPR) pathway play a key role in the pathogenesis of AML. ER stress is triggered by the accumulation of misfolded or unfolded proteins within the ER. This causes activation of the UPR to restore cellular homeostasis. However, the UPR can shift from promoting survival to inducing apoptos…

The integrated stress response in apicomplexan and trypanosomatid parasites: balancing survival and pathogenesis.

Parasites rely on their hosts for survival and replication and therefore face major challenges as they transition between hosts and encounter hostile microenvironments. Over evolution, these organisms have developed complex mechanisms to rapidly adapt to environmental fluctuations and to exploit host cellular machinery for persistence and dissemination. Among the pathways parasites deploy to cope with stress is the Integrated Stress Response (ISR), a conserved mechanism present in both parasites and their hosts, yet built on partially distinct molecular components. This shared but divergent pa

Pulmonary endoplasmic reticulum stress-scars, smoke, and suffocation.

Protein misfolding within the endoplasmic reticulum (ER stress) can be a cause or consequence of pulmonary disease. Mutation of proteins restricted to the alveolar type II pneumocyte can lead to inherited forms of pulmonary fibrosis, but even sporadic cases of pulmonary fibrosis appear to be strongly associated with activation of the unfolded protein response and/or the integrated stress response. Inhalation of smoke can impair protein folding and may be an important cause of pulmonary ER stress. Similarly, tissue hypoxia can lead to impaired protein homeostasis (proteostasis). But the mechani…