PKR Mediates the Mitochondrial Unfolded Protein Response through Double-Stranded RNA Accumulation under Mitochondrial Stress.

Mitochondrial stress, resulting from dysfunction and proteostasis disturbances, triggers the mitochondrial unfolded protein response (UPR), which activates gene encoding chaperones and proteases to restore mitochondrial function. Although ATFS-1 mediates mitochondrial stress UPR induction in . , the mechanisms relaying mitochondrial stress signals to the nucleus in mammals remain poorly defined.

Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation.

Tauopathies are neurodegenerative diseases caused by pathologic misfolded tau protein aggregation in the nervous system. Population studies implicate EIF2AK3 (eukaryotic translation initiation factor 2 alpha kinase 3), better known as PERK (protein kinase R-like endoplasmic reticulum kinase), as a genetic risk factor in several tauopathies. PERK is a key regulator of intracellular proteostatic mechanisms-unfolded protein response and integrated stress response.

The amino acid sensor GCN2 suppresses terminal oligopyrimidine (TOP) mRNA translation via La-related protein 1 (LARP1).

La-related protein 1 (LARP1) has been identified as a key translational inhibitor of terminal oligopyrimidine (TOP) mRNAs downstream of the nutrient sensing protein kinase complex, mTORC1. LARP1 exerts this inhibitory effect on TOP mRNA translation by binding to the mRNA cap and the adjacent 5'TOP motif, resulting in the displacement of the cap-binding protein eIF4E from TOP mRNAs. However, the involvement of additional signaling pathway in regulating LARP1-mediated inhibition of TOP mRNA translation is largely unexplored.

Protective Role of miR-34c in Hypoxia by Activating Autophagy through BCL2 Repression.

Hypoxia leads to significant cellular stress that has diverse pathological consequences such as cardiovascular diseases and cancers. MicroRNAs (miRNAs) are one of regulators of the adaptive pathway in hypoxia. We identified a hypoxia-induced miRNA, miR-34c, that was significantly upregulated in hypoxic human umbilical cord vein endothelial cells (HUVECs) and in murine blood vessels on day 3 of hindlimb ischemia (HLI).

Activation of ERK and p38 Reduces AZD8055-Mediated Inhibition of Protein Synthesis in Hepatocellular Carcinoma HepG2 Cell Line.

Protein synthesis is important for maintaining cellular homeostasis under various stress responses. In this study, we screened an anticancer drug library to select compounds with translational repression functions. AZD8055, an ATP-competitive mechanistic target of rapamycin complex 1/2 (mTORC1/2) inhibitor, was selected as a translational suppressor.

Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus.

Diabetes mellitus is characterized by the failure of insulin-secreting pancreatic β-cells (or β-cell death) due to either autoimmunity (type 1 diabetes mellitus) or failure to compensate for insulin resistance (type 2 diabetes mellitus; T2DM). In addition, mutations of critical genes cause monogenic diabetes. The endoplasmic reticulum (ER) is the primary site for proinsulin folding; therefore, ER proteostasis is crucial for both β-cell function and survival under physiological and pathophysiological challenges.

Vitamin D suppresses intestinal epithelial stemness via ER stress induction in intestinal organoids.

Background: Vitamin D is important for normal function of the intestinal epithelial cells (IECs). In this study, we aimed to investigate the effects of vitamin D on the differentiation, stemness, and viability of healthy IECs in intestinal organoids.

Methods: Intestinal organoids derived from mouse small intestine were treated with vitamin D, and the effects on intestinal stemness and differentiation were evaluated using real-time PCR and immunofluorescence staining of the distinct lineage markers.

Reduction in endoplasmic reticulum stress activates beige adipocytes differentiation and alleviates high fat diet-induced metabolic phenotypes.

Endoplasmic reticulum (ER) stress is closely associated with various metabolic diseases, such as obesity and diabetes. Development of beige/brite adipocytes increases thermogenesis and helps to reduce obesity. Although the relationship between ER stress and white adipocytes has been studied considerably, the possible role of ER stress and the unfolded protein response (UPR) induction in beige adipocytes differentiation remain to be investigated.

AMD1 is required for the maintenance of leukemic stem cells and promotes chronic myeloid leukemic growth.

Polyamines are critical elements in mammals, but it remains unknown whether adenosyl methionine decarboxylase (AMD1), a rate-limiting enzyme in polyamine synthesis, is required for myeloid leukemia. Here, we found that leukemic stem cells (LSCs) were highly differentiated, and leukemia progression was severely impaired in the absence of AMD1 in vivo. AMD1 was highly upregulated as chronic myeloid leukemia (CML) progressed from the chronic phase to the blast crisis phase, and was associated with the poor prognosis of CML patients.

Stress Granule Formation Attenuates RACK1-Mediated Apoptotic Cell Death Induced by Morusin.

Stress granules are membraneless organelles composed of numerous components including ribonucleoproteins. The stress granules are characterized by a dynamic complex assembly in response to various environmental stressors, which has been implicated in the coordinated regulation of diverse biological pathways, to exert a protective role against stress-induced cell death. Here, we show that stress granule formation is induced by morusin, a novel phytochemical displaying antitumor capacity through barely known mechanisms.

Biallelic mutations in ABCB1 display recurrent reversible encephalopathy.

The clinical phenotype linked with mutations in ABCB1, encoding P-glycoprotein, has never been reported. Here, we describe twin sisters with biallelic mutations in ABCB1 who showed recurrent reversible encephalopathy accompanied by acute febrile or afebrile illness. Whole-exome sequencing was performed on one of the twin and her healthy parents, and revealed compound heterozygous loss-of-function variants in ABCB1.

MicroRNA-142-5p is Up-regulated on Allogeneic Immune Responses and Up-regulates MHC Class II Expression in Human Umbilical Vein Endothelial Cells.

Purpose: MicroRNA could be biomarker and therapeutic target for rejection. The aim of this study was to investigate the role of miR-142-5p in allogeneic immune responses using in vitro and in vivo models.

Materials And Methods: Primary and immortalized human umbilical vein endothelial cells (HUVECs) were cultured with unrelated blood mononuclear cells to induce allogeneic immune responses.

Hyperthermia Disturbs and Delays Spontaneous Differentiation of Human Embryoid Bodies.

Various types of stress stimuli have been shown to threaten the normal development of embryos during embryogenesis. Prolonged heat exposure is the most common stressor that poses a threat to embryo development. Despite the extensive investigation of heat stress control mechanisms in the cytosol, the endoplasmic reticulum (ER) heat stress response remains unclear.

Mitophagy deficiency increases NLRP3 to induce brown fat dysfunction in mice.

Although macroautophagy/autophagy deficiency causes degenerative diseases, the deletion of essential autophagy genes in adipocytes paradoxically reduces body weight. Brown adipose tissue (BAT) plays an important role in body weight regulation and metabolic control. However, the key cellular mechanisms that maintain BAT function remain poorly understood.

Characterization of Endoplasmic Reticulum (ER) in Human Pluripotent Stem Cells Revealed Increased Susceptibility to Cell Death upon ER Stress.

Human pluripotent stem cells (hPSCs), such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have a well-orchestrated program for differentiation and self-renewal. However, the structural features of unique proteostatic-maintaining mechanisms in hPSCs and their features, distinct from those of differentiated cells, in response to cellular stress remain unclear. We evaluated and compared the morphological features and stress response of hPSCs and fibroblasts.

ER stress reliever enhances functionalities of in vitro cultured hepatocytes.

Endoplasmic reticulum stress (ER stress) leads an unfolded protein response (UPR) which results in internal cellular responses such as proteostasis and protein clearance. Recently, several reports demonstrated that the ER stress in stem cells could affect their stemness and fates to differentiate into certain lineages. However, the potential for controlling differentiation and function of cells by regulating ER stress needs to be further addressed.

PERK-Mediated eIF2α Phosphorylation Contributes to The Protection of Dopaminergic Neurons from Chronic Heat Stress in .

Environmental high-temperature heat exposure is linked to physiological stress such as disturbed protein homeostasis caused by endoplasmic reticulum (ER) stress. Abnormal proteostasis in neuronal cells is a common pathological factor of Parkinson's disease (PD). Chronic heat stress is thought to induce neuronal cell death during the onset and progression of PD, but the exact role and mechanism of ER stress and the activation of the unfolded protein response (UPR) remains unclear.

ER Stress Induces Cell Cycle Arrest at the G2/M Phase Through eIF2α Phosphorylation and GADD45α.

Endoplasmic reticulum (ER) stress is known to influence various cellular functions, including cell cycle progression. Although it is well known how ER stress inhibits cell cycle progression at the G1 phase, the molecular mechanism underlying how ER stress induces G2/M cell cycle arrest remains largely unknown. In this study, we found that ER stress and subsequent induction of the UPR led to cell cycle arrest at the G2/M phase by reducing the amount of cyclin B1.

PERK-mediated induction of microRNA-483 disrupts cellular ATP homeostasis during the unfolded protein response.

Endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR), which reduces levels of misfolded proteins. However, if ER homeostasis is not restored and the UPR remains chronically activated, cells undergo apoptosis. The UPR regulator, PKR-like endoplasmic reticulum kinase (PERK), plays an important role in promoting cell death when persistently activated; however, the underlying mechanisms are poorly understood.

Cytotoxicity of Human Hepatic Intrasinusoidal CD56 Natural Killer Cells against Hepatocellular Carcinoma Cells.

Hepatic intrasinusoidal (HI) natural killer (NK) cells from liver perfusate have unique features that are similar to those of liver-resident NK cells. Previously, we have reported that HI CD56 NK cells effectively degranulate against SNU398 hepatocellular carcinoma (HCC) cells. Thus, the aim of this study was to further investigate the phenotype and function of HI NK cells.

Modulation of Protein Synthesis by eIF2α Phosphorylation Protects Cell from Heat Stress-Mediated Apoptosis.

Global warming poses a considerable threat to human health, necessitating a proper understanding of mechanisms underlying cell death in the pathogenesis of heat-related diseases. Although mechanisms governing cytoplasmic response to heat are well understood, processes regulating cellular response to disruption of proteostasis in the endoplasmic reticulum (ER) due to heat stress remain unclear. The current study reveals that hyperthermic conditions may lead to a disturbance of ER homeostasis, also known as ER stress.

MiR-9 Controls Chemotactic Activity of Cord Blood CD34⁺ Cells by Repressing CXCR4 Expression.

Improved approaches for promoting umbilical cord blood (CB) hematopoietic stem cell (HSC) homing are clinically important to enhance engraftment of CB-HSCs. Clinical transplantation of CB-HSCs is used to treat a wide range of disorders. However, an improved understanding of HSC chemotaxis is needed for facilitation of the engraftment process.

Carbon monoxide regulates glycolysis-dependent NLRP3 inflammasome activation in macrophages.

Low dose of carbon monoxide (CO) has anti-inflammatory role through various signaling pathways. Cellular metabolism has been implicated in the activation of inflammation in immune cells. However, the mechanisms by which CO-dependent metabolic regulation affect the immune response remain unclear.