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Development of TRIB3-Based Therapy as a Gene-Independent Approach to Treat Retinal Degenerative Disorders.

Inherited retinal degeneration (RD) constitutes a heterogeneous group of genetic retinal degenerative disorders. The molecular mechanisms underlying RD encompass a diverse spectrum of cellular signaling, with the unfolded protein response (UPR) identified as a common signaling pathway chronically activated in degenerating retinas. TRIB3 has been recognized as a key mediator of the PERK UPR arm, influencing various metabolic pathways, such as insulin signaling, lipid metabolism, and glucose homeostasis, by acting as an AKT pseudokinase that prevents the activation of the AKT → mTOR axis. This s…

Spliced or Unspliced, That Is the Question: The Biological Roles of XBP1 Isoforms in Pathophysiology.

X-box binding protein 1 (XBP1) is a member of the CREB/ATF basic region leucine zipper family transcribed as the unspliced isoform (XBP1-u), which, upon exposure to endoplasmic reticulum stress, is spliced into its spliced isoform (XBP1-s). XBP1-s interacts with the cAMP response element of major histocompatibility complex class II gene and plays critical role in unfolded protein response (UPR) by regulating the transcriptional activity of genes involved in UPR. XBP1-s is also involved in other physiological pathways, including lipid metabolism, insulin metabolism, and differentiation of immun…

The Juvenile Parkinson's Disease Mutation C212Y Impairs Mitochondrial Homeostasis in a Caenorhabditis elegans Model.

Inherited Parkinson's disease (PD) often involves missense mutations in the PRKN2 gene, encoding for Parkin protein. The PDR-1 protein is th … and mitochondrial membrane potential. However, these phenotypes did not activate the mitochondrial unfolded protein response. Pan-neuronal analysis revealed decreased mitophagy. Dopaminergic neurodegeneration in aged animals was not enhanced when compared to WT. Our findings suggest that analysis of the recessive missense point mutations found in early-onset PD using the …

baz-2 enhances systemic proteostasis in vivo by regulating acetylcholine metabolism.

Neurodegenerative disorders, such as Alzheimer's disease (AD) or Huntington's disease (HD), are linked to protein aggregate neurotoxicity. A … reduction or ectopic ACh treatment augments proteostasis via induction of the endoplasmic reticulum unfolded protein response and the ubiquitin proteasome system.

The UPR sensor IRE1α and the adenovirus E3-19K glycoprotein sustain persistent and lytic infections.

Persistent viruses cause chronic disease, and threaten the lives of immunosuppressed individuals. Here, we elucidate a mechanism supporting the persistence of human adenovirus (AdV), a virus that can kill immunosuppressed patients. Cell biological analyses, genetics and chemical interference demonstrate that one of five AdV membrane proteins, the E3-19K glycoprotein specifically triggers the unfolded protein response (UPR) sensor IRE1α in the endoplasmic reticulum (ER), but not other UPR sensors, such as protein kinase R-like ER kinase (PERK) and activating transcription factor 6 (ATF6). The E…

A PERK-miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival.

The unfolded protein response (UPR) is a stress-activated signalling pathway that regulates cell proliferation, metabolism and survival. The circadian clock coordinates metabolism and signal transduction with light/dark cycles. We explore how UPR signalling interfaces with the circadian clock. UPR activation induces a 10 h phase shift in circadian oscillations through induction of miR-211, a PERK-inducible microRNA that transiently suppresses both Bmal1 and Clock, core circadian regulators. Molecular investigation reveals that miR-211 directly regulates Bmal1 and Clock via distinct mechanisms.…

Derlin-2-deficient mice reveal an essential role for protein dislocation in chondrocytes.

Protein quality control is a balance between chaperone-assisted folding and removal of misfolded proteins from the endoplasmic reticulum (ER). Cell-based assays have been used to identify key players of the dislocation machinery, including members of the Derlin family. We generated conditional knockout mice to examine the in vivo role of Derlin-2, a component that nucleates cellular dislocation machinery. In most Derlin-2-deficient tissues, we found constitutive upregulation of ER chaperones and IRE-1-mediated induction of the unfolded protein response. The IRE-1/XBP-1 pathway is required for …

Вирус Западного Нила и вирусные инфекции Зики вызывают резкие образования в гениальных потомках человека и в клетках A549.

UNLABELELED: Ранее было замечено, что вирусные репликации зики (VRV) имеют асимметричное скопление с одной стороны ядра в инфицированных Huh7, A549 и h-NPC. Инфекции вируса Западного Нила (ВНВ) в этих клетках также вызывают асимметричное группирование VRV. Были исследованы последовательные ответы ячеек, ведущие к асимметричной группировке ВНВ и ЗИКВ VRV. Обе инфекции активировали белковую реакцию на клетку (УПО), о чем свидетельствует усиление ПРФ78, главного регулятора УПО, и активация отделения ПЕРК УПО (p-PERK-p-eIF2α-GADD34). Кроме того, был вызван рост ацетилации микротубуля (MT). По мере

Совпадение в аннотации оригинала
UNLABELLED: Zika viral replication vesicles (VRVs) were previously observed to cluster asymmetrically on one side of the nucleus in infected … etric clustering of the WNV and ZIKV VRVs were investigated. Both infections activated the cellular unfolded protein response (UPR), as indicated by increased expression of GRP78, the master regulator of UPR, and activation of the PERK branch of the UPR (p-PERK-p-eIF2α-GADD34). Increased microtubule (MT) acetylation was also induced. As the infection progressed, the level …

Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies.

Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge i … anisms that are involved in the chemotherapy response including apoptosis, macro-autophagy, and the unfolded protein response. Finally, we discuss in vivo mouse and zebrafish models and in vitro three-dimensional bioengineering models of rhabdomyosarcoma to screen future therapeutic approaches and promote muscle regeneration.

Endoplasmic reticulum as a target in cardiovascular diseases: Is there a role for flavonoids?

Flavonoids are found in natural health products and plant-based foods. The flavonoid molecules contain a 15-carbon skeleton with the particu … ulum and then arise in endoplasmic reticulum stress. Constant endoplasmic reticulum stress triggers unfolded protein response (UPR), which ultimately causes apoptosis. Research has shown that endoplasmic reticulum stress plays a critical part in the pathogenesis of several cardiovascular diseases, including diabetic cardiomyopathy, ischemic heart disease, heart failure, ao …

(-)- Epigallocatechin-3-gallate induces GRP78 accumulation in the ER and shifts mesothelioma constitutive UPR into proapoptotic ER stress.

GRP78 is a molecular chaperone of the endoplasmic reticulum (ER) that aids proper folding of nascent polypeptides. When unfolded proteins accumulate, GRP78 triggers unfolded protein response (UPR), involving activation of transcription factors like XBP1 and CHOP that may restore cell homeostasis. Increased expression of GRP78 and mild UPR can be constitutive in cancer cells, hindering apoptosis, and promoting cell survival, for example, by GRP78 relocation to the plasma membrane that activates MAPK and PI3 K/AKT pathways. These processes are thought to favor the insurgence of chemoresistance a…

Are Major Dementias Triggered by Poor Blood Flow to the Brain? Theoretical Considerations.

There is growing evidence that chronic brain hypoperfusion plays a central role in the development of Alzheimer's disease (AD) long before d … levels of unfolded or misfolded proteins overwhelm and downregulate the neuroprotective activity of unfolded protein response which is unable to get rid of dysfunctional organelles such as damaged mitochondria and malformed proteins at the synapse. The endpoint of this neuropathologic process results in damaged synapses, impaired neurotransmission, cognitive decline, and d …

Leveraging ANXA1 to enhance recombinant protein yields in CHO cells: A UPR-Mediated bioprocessing approach.

Chinese hamster ovary (CHO) cells undergo endoplasmic reticulum stress (ERS) during intensive recombinant protein production, triggering the unfolded protein response (UPR) to balance cell survival and protein output. Nevertheless, key regulatory components of this process remain incompletely characterized. In this study, we demonstrate that Annexin A1 (ANXA1) functions as a UPR suppressor in CHO cells. Employing the PiggyBac transposon system, we generated a stable ANXA1-knockdown cell line exhibiting a 4.5-fold increase in recombinant antibody expression and a 4.2-fold increase in specific p…

Unveiling OASIS family as a key player in hypoxia-ischemia cases induced by cocaine using generative adversarial networks.

Repeated cocaine use poses many serious health risks to users. One of the risks is hypoxia and ischemia (HI). To restore the biological syst … ily, one of the Creb family, is a key player in various defense mechanisms such as angiogenesis and unfolded protein response against the HI state by unveiling hidden mRNA expression profiles. Furthermore, we identified mysterious kinases in the OASIS family and are able to explain why the prefrontal cortex and hippocampus are vulnerable to HI at the genetic level.

Converging pathways in the occurrence of endoplasmic reticulum (ER) stress in Huntington's disease.

A variety of neurological diseases including Huntington's disease (HD), Alzheimer's disease and Parkinson's disease share common neuropathology, primarily featuring the presence of abnormal protein inclusions containing specific misfolded proteins. Mutations leading to expansion of a poly-glutamine track in Huntingtin cause HD, and trigger its misfolding and aggregation. Recent evidence indicates that alterations in the secretory pathway, in particular the endoplasmic reticulum (ER), are emerging features of HD. Although it is not clear how cytoplasmic/nuclear located mutant Huntingtin alters

Mitochondrial stress induces transcription of cytosolic and mitochondrial protein synthesis components via NHR-180.

The mitochondrial unfolded protein response (UPRmt), which promotes mitochondrial biogenesis and proteostasis, is regulated by the transcription factor ATFS-1. In C. elegans, impaired atfs-1 expression perturbs mitochondrial function and slows development. Here, using an RNAi suppressor screen, we find that inhibition of the nuclear hormone receptor NHR-180 increases mitochondrial function and developmental rate in atfs-1(null) worms. NHR-180 levels increase and become more nuclear-localized during mitochondrial dysfunction, inducing transcription of genes required for protein synthesis on cyt…

Vancomycin eliminates gut deoxycholic acid, restoring ER proteostasis in ILC2s and relieving colitis.

Ulcerative colitis (UC) remission is marked by gut microbiota restructuring, but how microbial metabolites influence immune-mediated tissue … e protein 2 (TMX2). This interaction disrupts TMX2's role in protein folding, triggering unresolved unfolded protein response via hyperactivation of PERK/eIF2α signaling, which suppresses the production of pro-healing molecules by ILC2s. Pharmacological inhibition of PERK phosphorylation restores ILC2 function and accelerates colitis resolution. Our work uncovers a pathoge …

Z-α1-antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state.

Misfolding of secretory proteins in the endoplasmic reticulum (ER) features in many human diseases. In α1-antitrypsin deficiency, the pathogenic Z variant aberrantly assembles into polymers in the hepatocyte ER, leading to cirrhosis. We show that α1-antitrypsin polymers undergo a liquid:solid phase transition, forming a protein matrix that retards mobility of ER proteins by size-dependent molecular filtration. The Z-α1-antitrypsin phase transition is promoted during ER stress by an ATF6-mediated unfolded protein response. Furthermore, the ER chaperone calreticulin promotes Z-α1-antitrypsin sol…

Transcriptomics-Based Screening Identifies Pharmacological Inhibition of Hsp90 as a Means to Defer Aging.

Aging strongly influences human morbidity and mortality. Thus, aging-preventive compounds could greatly improve our health and lifespan. Her … ved the survival of C. elegans under proteotoxic stress, and its benefits depended on the cytosolic unfolded protein response-inducing transcription factor HSF-1. Taken together, our method represents an innovative geroprotector screening approach and was able to identify a class that acts by improving protein homeostasis.

Mitochondrial fission facilitates the selective mitophagy of protein aggregates.

Within the mitochondrial matrix, protein aggregation activates the mitochondrial unfolded protein response and PINK1-Parkin-mediated mitophagy to mitigate proteotoxicity. We explore how autophagy eliminates protein aggregates from within mitochondria and the role of mitochondrial fission in mitophagy. We show that PINK1 recruits Parkin onto mitochondrial subdomains after actinonin-induced mitochondrial proteotoxicity and that PINK1 recruits Parkin proximal to focal misfolded aggregates of the mitochondrial-localized mutant ornithine transcarbamylase (ΔOTC). Parkin colocalizes on polarized mito…