scholarly journals sMEK1 promotes crosstalk between IRE1 and Akt signaling pathway: Evidence for a novel IRE1/sMEK1/Akt complex

2021 ◽  
Author(s):  
ozaira qadri ◽  
Samirul Bashir ◽  
Mariam Banday ◽  
Nazia Hilal ◽  
Khalid M Fazili
Keyword(s):  
Protein Kinase ◽  
Er Stress ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Ternary Complex ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Unfolded Protein ◽  
Central Molecule ◽  
Protein Response

ER is facilitated with a dynamic cellular pathway namely Unfolded Protein Response (UPR): an adaptive signalling mechanism that maintains proteostasis in response to ER stress. IRE1 is one of the three transmembrane sensors of UPR with dual protein kinase and ribonuclease activities. IRE1 acts as a central molecule of UPR, which associates with a number of proteins that either regulate its activity or connect it to other pathways. Here, we report sMEK1 and Akt as novel interacting partners of IRE1 which associate to orchestrate the IRE1 and Akt signalling networks. Our study revealed that ER stress negatively regulates Akt through IRE1 protein. We found that IRE1/sMEK1/Akt form a ternary complex, which results in the dephosphorylation of Akt by protein phosphotase sMEK1 in presence of activated IRE1. Together, this study highlights the UPR/Akt link by delineating the molecular mechanism along with giving insights into the overall impact of this interaction.

scholarly journals Nonstructural 3 Protein of Hepatitis C Virus Modulates the Tribbles Homolog 3/Akt Signaling Pathway for Persistent Viral Infection

2016 ◽  
Vol 90 (16) ◽  
pp. 7231-7247 ◽  
Author(s):  
Si C. Tran ◽  
Tu M. Pham ◽  
Lam N. Nguyen ◽  
Eun-Mee Park ◽  
Yun-Sook Lim ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Viral Infection ◽  
Er Stress ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Hcv Rna ◽  
Akt Signaling Pathway ◽  
Protein Levels ◽  
Persistent Viral Infection ◽  
Infected Cells

ABSTRACTHepatitis C virus (HCV) infection often causes chronic hepatitis, liver cirrhosis, and ultimately hepatocellular carcinoma. However, the mechanisms underlying HCV-induced liver pathogenesis are still not fully understood. By transcriptome sequencing (RNA-Seq) analysis, we recently identified host genes that were significantly differentially expressed in cell culture-grown HCV (HCVcc)-infected cells. Of these, tribbles homolog 3 (TRIB3) was selected for further characterization. TRIB3 was initially identified as a binding partner of protein kinase B (also known as Akt). TRIB3 blocks the phosphorylation of Akt and induces apoptosis under endoplasmic reticulum (ER) stress conditions. HCV has been shown to enhance Akt phosphorylation for its own propagation. In the present study, we demonstrated that both mRNA and protein levels of TRIB3 were increased in the context of HCV replication. We further showed that promoter activity of TRIB3 was increased by HCV-induced ER stress. Silencing of TRIB3 resulted in increased RNA and protein levels of HCV, whereas overexpression of TRIB3 decreased HCV replication. By employing an HCV pseudoparticle entry assay, we further showed that TRIB3 was a negative host factor involved in HCV entry. Bothin vitrobinding and immunoprecipitation assays demonstrated that HCV NS3 specifically interacted with TRIB3. Consequently, the association of TRIB3 and Akt was disrupted by HCV NS3, and thus, TRIB3-Akt signaling was impaired in HCV-infected cells. Moreover, HCV modulated TRIB3 to promote extracellular signal-regulated kinase (ERK) phosphorylation, activator protein 1 (AP-1) activity, and cell migration. Collectively, these data indicate that HCV exploits the TRIB3-Akt signaling pathway to promote persistent viral infection and may contribute to HCV-mediated pathogenesis.IMPORTANCETRIB3 is a pseudokinase protein that acts as an adaptor in signaling pathways for important cellular processes. So far, the functional involvement of TRIB3 in virus-infected cells has not yet been demonstrated. We showed that both mRNA and protein expression levels of TRIB3 were increased in the context of HCV RNA replication. Gene silencing of TRIB3 increased HCV RNA and protein levels, and thus, overexpression of TRIB3 decreased HCV replication. TRIB3 is known to promote apoptosis by negatively regulating the Akt signaling pathway under ER stress conditions. Most importantly, we demonstrated that the TRIB3-Akt signaling pathway was disrupted by NS3 in HCV-infected cells. These data provide evidence that HCV modulates the TRIB3-Akt signaling pathway to establish persistent viral infection.

scholarly journals Herpes Simplex Virus 1 UL41 Protein Suppresses the IRE1/XBP1 Signal Pathway of the Unfolded Protein Response via Its RNase Activity

2016 ◽  
Vol 91 (4) ◽  
Author(s):  
Pengchao Zhang ◽  
Chenhe Su ◽  
Zhangtao Jiang ◽  
Chunfu Zheng
Keyword(s):  
Er Stress ◽  
Molecular Mechanism ◽  
Signal Pathway ◽  
Herpes Simplex Virus 1 ◽  
Unfolded Protein ◽  
Xbp1 Mrna ◽  
The Unfolded Protein Response ◽  
Simplex Virus ◽  
Protein Response ◽  
Hsv 1

ABSTRACT During viral infection, accumulation of viral proteins can cause stress in the endoplasmic reticulum (ER) and trigger the unfolded protein response (UPR) to restore ER homeostasis. The inositol-requiring enzyme 1 (IRE1)-dependent pathway is the most conserved of the three UPR signal pathways. Upon activation, IRE1 splices out an intron from the unspliced inactive form of X box binding protein 1 [XBP1(u)] mRNA and produces a transcriptionally potent spliced form [XBP1(s)]. Previous studies have reported that the IRE1/XBP1 pathway is inhibited upon herpes simplex virus 1 (HSV-1) infection; however, the underlying molecular mechanism is still elusive. Here, we uncovered a role of the HSV-1 UL41 protein in inhibiting the IRE1/XBP1 signal pathway. Ectopic expression of UL41 decreased the expression of XBP1 and blocked XBP1 splicing activation induced by the ER stress inducer thapsigargin. Wild-type (WT) HSV-1, but not the UL41-null mutant HSV-1 (R2621), decreased XBP1 mRNA induced by thapsigargin. Nevertheless, infection with both WT HSV-1 and R2621 without drug pretreatment could reduce the mRNA and protein levels of XBP1(s), and additional mechanisms might contribute to this inhibition of XBP1(s) during R2621 infection. Taking these findings together, our results reveal XBP1 as a novel target of UL41 and provide insights into the mechanism by which HSV-1 modulates the IRE1/XBP1 pathway. IMPORTANCE During viral infection, viruses hijack the host translation apparatus to produce large amounts of viral proteins, which leads to ER stress. To restore ER homeostasis, cells initiate the UPR to alleviate the effects of ER stress. The IRE1/XBP1 pathway is the most conserved UPR branch, and it activates ER-associated protein degradation (ERAD) to reduce the ER load. The IRE1/XBP1 branch is repressed during HSV-1 infection, but little is known about the underlying molecular mechanism. Our results show for the first time that UL41 suppresses the IRE1/XBP1 signal pathway by reducing the accumulation of XBP1 mRNA, and characterization of the underlying molecular mechanism provides new insight into the modulation of UPR by HSV-1.

scholarly journals Downregulation of cAMP-Dependent Protein Kinase Inhibitor-b Promotes Preeclampsia by Decreasing Phosphorylated Akt

2020 ◽  
Vol 28 (1) ◽  
pp. 178-185
Author(s):  
Chunfeng Liu ◽  
Hao Wang ◽  
Mo Yang ◽  
Yiheng Liang ◽  
Li Jiang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Matrix Metalloproteinase ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
Akt Signaling ◽  
Migration And Invasion ◽  
Akt Signaling Pathway ◽  
Dependent Protein Kinase ◽  
Phosphorylated Akt ◽  
Dependent Protein

AbstractPreeclampsia is a multi-system disease that is unique to human pregnancy. Impaired extravillous trophoblast migration and invasion accompanied by poor spiral vascular remodeling is thought to be the initial reason. This study investigated cAMP-dependent protein kinase inhibitor-b(PKIB) expression in placentas and its involvement in the pathogenesis of PE. We used immunohistochemistry and western blotting to calculate PKIB levels in the placentas. Then we knocked down PKIB by siRNA and used real-time cell analysis to assess the invasion and migration ability of trophoblasts. Tube formation assay and spheroid sprouting assay were utilized to identify the ability to form vessels of trophoblasts. At last, western blotting was used to demonstrate the level of phosphorylated Akt, as well as downstream-related genes of Akt signaling pathway in trophoblasts. We first found that PKIB expression level was lower in the PE placentas than in the normal placentas. In addition, we found that downregulation of PKIB can inhibit the migration, invasion, and the ability to form vessels of HTR8/SVneo cells. Downregulation of PKIB leaded to a decrease in phosphorylated Akt, as well as downstream proteins such as matrix metalloproteinase 2, matrix metalloproteinase 9, and glycogen synthase kinase 3β, which are related to migration and invasion. Our study revealed that the downregulation of PKIB expression resulted in decreased migration, invasion, and vessel formation ability by regulating Akt signaling pathway in placental trophoblasts in PE.

scholarly journals HY5, a positive regulator of light signaling, negatively controls the unfolded protein response inArabidopsis

2017 ◽  
Vol 114 (8) ◽  
pp. 2084-2089 ◽  
Author(s):  
Ganesh M. Nawkar ◽  
Chang Ho Kang ◽  
Punyakishore Maibam ◽  
Joung Hun Park ◽  
Young Jun Jung ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Molecular Mechanism ◽  
26S Proteasome ◽  
Light Signaling ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
The Unfolded Protein Response ◽  
Protein Response

Light influences essentially all aspects of plant growth and development. Integration of light signaling with different stress response results in improvement of plant survival rates in ever changing environmental conditions. Diverse environmental stresses affect the protein-folding capacity of the endoplasmic reticulum (ER), thus evoking ER stress in plants. Consequently, the unfolded protein response (UPR), in which a set of molecular chaperones is expressed, is initiated in the ER to alleviate this stress. Although its underlying molecular mechanism remains unknown, light is believed to be required for the ER stress response. In this study, we demonstrate that increasing light intensity elevates the ER stress sensitivity of plants. Moreover, mutation of the ELONGATED HYPOCOTYL 5 (HY5), a key component of light signaling, leads to tolerance to ER stress. This enhanced tolerance ofhy5plants can be attributed to higher expression of UPR genes. HY5 negatively regulates the UPR by competing with basic leucine zipper 28 (bZIP28) to bind to the G-box–like element present in the ER stress response element (ERSE). Furthermore, we found that HY5 undergoes 26S proteasome-mediated degradation under ER stress conditions. Conclusively, we propose a molecular mechanism of crosstalk between the UPR and light signaling, mediated by HY5, which positively mediates light signaling, but negatively regulates UPR gene expression.

scholarly journals Asiatic acid attenuates hypertrophic and fibrotic differentiation of articular chondrocytes via AMPK/PI3K/AKT signaling pathway

2020 ◽  
Author(s):  
Na Liu ◽  
Dejie Fu ◽  
Junjun Yang ◽  
Pingju Liu ◽  
Xiongbo Song ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Type I Collagen ◽  
Articular Chondrocytes ◽  
Akt Signaling ◽  
Type I ◽  
Asiatic Acid ◽  
Akt Signaling Pathway ◽  
Chondrocyte Hypertrophy ◽  
Chondrogenic Phenotype

Abstract Background: Osteoarthritis (OA), the most common joint disorder, is characterized by a progressive degradation of articular cartilage. Increasing evidence suggests that OA is closely associated with cartilage pathologies including chondrocyte hypertrophy and fibrosis. Methods: In this study, we showed that asiatic acid (AA) treatment reduced chondrocyte hypertrophy and fibrosis. First, the cytotoxicity of AA (0, 5, 10, and 20 μM) to chondrocytes was evaluated, and 5 μM was selected for subsequent experiments. Then, we detected the gene and protein level of chondrocyte hypertrophic markers including type X collagen (COL-X), matrix metalloproteinase - 13 (MMP-13), alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and chondrocyte fibrosis markers including type I collagen (COL-Ι) and alpha-smooth muscle actin (α-SMA), and chondrogenic markers including SRY-related HMG box 9 (SOX9), type II collagen (COL-II) and aggrecan (ACAN). Further, we tested the mechanism of AA on inhibiting chondrocyte hypertrophy and fibrosis. Finally, we verified the results in an anterior cruciate ligament transection (ACLT) rat OA model.Results: We found that AA treatment inhibited the hypertrophic and fibrotic phenotype of chondrocytes, without affecting the chondrogenic phenotype. Moreover, we found that AA treatment activated AMP-activated protein kinase (AMPK) and inhibited phosphoinositide-3 kinase/protein kinase B (PI3K/AKT) signaling pathway in vitro. The results in an ACLT-rat OA model also indicated that AA significantly attenuated chondrocyte hypertrophy and fibrosis. Conclusion: AA treatment could reduce hypertrophic and fibrotic differentiation, and maintain the chondrogenic phenotype of articular chondrocytes by targeting the AMPK/PI3K/AKT signaling pathway. Our study suggested that AA might be a prospective drug component that targets hypertrophic and fibrotic chondrocytes for OA treatment.

scholarly journals Anacardic acid induces cell apoptosis of prostatic cancer through autophagy by ER stress/DAPK3/Akt signaling pathway

2017 ◽  
Vol 38 (3) ◽  
pp. 1373-1382 ◽  
Author(s):  
Jing Tan ◽  
Xianzhen Jiang ◽  
Guangming Yin ◽  
Leye He ◽  
Jianye Liu ◽  
...  
Keyword(s):  
Er Stress ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Prostatic Cancer ◽  
Akt Signaling ◽  
Anacardic Acid ◽  
Akt Signaling Pathway

scholarly journals Distinct roles of activating transcription factor 6 (ATF6) and double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) in transcription during the mammalian unfolded protein response

2002 ◽  
Vol 366 (2) ◽  
pp. 585-594 ◽  
Author(s):  
Tetsuya OKADA ◽  
Hiderou YOSHIDA ◽  
Rieko AKAZAWA ◽  
Manabu NEGISHI ◽  
Kazutoshi MORI
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Protein Kinase ◽  
Er Stress ◽  
Double Stranded Rna ◽  
Unfolded Protein ◽  
Genes Encoding ◽  
Membrane Bound ◽  
Activating Transcription Factor ◽  
Protein Response

In response to accumulation of unfolded proteins in the endoplasmic reticulum (ER), a homoeostatic response, termed the unfolded protein response (UPR), is activated in all eukaryotic cells. The UPR involves only transcriptional regulation in yeast, and approx. 6% of all yeast genes, encoding not only proteins to augment the folding capacity in the ER, but also proteins working at various stages of secretion, are induced by ER stress [Travers, Patil, Wodicka, Lockhart, Weissman and Walter (2000) Cell (Cambridge, Mass.) 101, 249–258]. In the present study, we conducted microarray analysis of HeLa cells, although our analysis covered only a small fraction of the human genome. A great majority of human ER stress-inducible genes (approx. 1% of 1800 genes examined) were classified into two groups. One group consisted of genes encoding ER-resident molecular chaperones and folding enzymes, and these genes were directly regulated by the ER-membrane-bound transcription factor activating transcription factor (ATF) 6. The ER-membrane-bound protein kinase double-stranded RNA-activated protein kinase-like ER kinase (PERK)-mediated signalling pathway appeared to be responsible for induction of the remaining genes, which are not involved in secretion, but may be important after cellular recovery from ER stress. In higher eukaryotes, the PERK-mediated translational-attenuation system is known to operate in concert with the transcriptional-induction system. Thus we propose that mammalian cells have evolved a strategy to cope with ER stress different from that of yeast cells.

scholarly journals Regulation of the unfolded protein response transducer IRE1α by SERPINH1 aggravates periodontitis with diabetes mellitus via prolonged ER stress

2021 ◽  
Author(s):  
Mengdi Li ◽  
Shuheng Huang ◽  
Yong Zhang ◽  
Zhi Song ◽  
Haijun Fu ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Er Stress ◽  
Signaling Pathway ◽  
Rna Seq ◽  
Unfolded Protein ◽  
Periodontal Inflammation ◽  
Gingival Epithelium ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Background The hyperglycemic microenvironment induced by diabetes mellitus aggravates the inflammatory response, in which the inositol-requiring enzyme-1α (IRE1α) signal transduction pathway of the unfolded protein response (UPR) participates. This study aimed to investigate the mechanism by which hyperglycemia regulates the IRE1α signaling pathway and affects endoplasmic reticulum (ER) homeostasis in human gingival epithelium in periodontitis with diabetes mellitus (DP). Methods Human gingival epithelium samples from healthy subjects, subjects with periodontitis and subjects with DP were collected, in vitro cultures of human gingival epithelial cells were challenged with a hyperglycemic microenvironment to observe the effects of diabetes on periodontal inflammation and to assess UPR-IRE1α signaling in human gingival epithelium in DP. Subsequently, RNA sequencing (RNA-seq) data was analyzed to investigate the expression of ER-related genes in human gingival epithelium. Furthermore, to explore the key role of serpin family H member 1 (SERPINH1) in the regulation of UPR-IRE1α signaling in a hyperglycemic microenvironment, experiments in SERPINH1-knockdown and SERPINH1-overexpression models were established in vitro. Results Diabetes causes a hyperinflammatory response in human gingival epithelium, which accelerates periodontal inflammation. A hyperglycemic microenvironment inhibited the inositol-requiring enzyme-1α / X-box binding protein 1 (IRE1α/XBP1) axis, decreased the expression of glucose regulated protein 78 (GRP78), and ultimately impaired the UPR, causing ER stress to be prolonged or more severe in human gingival epithelium. The RNA-seq and experiments revealed that the mechanism by which periodontitis is aggravated in individuals with diabetes mellitus may involve decreased SERPINH1 expression. SERPINH1 might act as an activator of IRE1α, maintaining human gingival epithelium homeostasis, suppressing nuclear factor-κB signaling pathway and reducing NOD-like receptor, pyrin domain containing protein 3 (NLRP3) and interleukin-1 beta (IL-1β) expression by preventing prolonged ER stress induced by high-glucose conditions. Conclusion Regulation of the UPR transducer IRE1α by SERPINH1 alleviates DP by mitigating prolonged ER stress.

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