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Inositol-Requiring Enzyme-1 Regulates Phosphoinositide Signaling Lipids and Macrophage Growth

ABSTRACT: 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 plays an unprecedented role in regulating phosphatidylinositide-derived signaling lipid metabolites and has profound impact on the downstream signaling mediated by the mammalian target of rapamycin (mTOR). This cross-talk between UPR and mTOR pathways occurs through the unconventional maturation of microRNA (miR) 2137 by IRE1's RNase activity. Futhermore, phosphatidylinositol (3,4,5) phosphate (PI(3,4,5)P3) 5-phosphatase-2 (INPPL1) is a direct target of miR-2137, which controls PI(3,4,5)P3 levels in macrophages. The modulation of cellular PI(3,4,5)P3/PIP2 ratio and anabolic mTOR signaling by the IRE1-induced miR-2137 demonstrates how the ER can provide a critical input into cell growth decisions.

SUBMITTER: Dr. Syed Muhammad Hamid

PROVIDER: S-SCDT-EMBOR-2020-51462V1 | biostudies-other |

REPOSITORIES: biostudies-other

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

Project description: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 plays an unprecedented role in regulating phosphatidylinositide-derived signaling lipid metabolites and has profound impact on the downstream signaling mediated by the mammalian target of rapamycin (mTOR). This cross-talk between UPR and mTOR pathways occurs through the unconventional maturation of microRNA (miR) 2137 by IRE1's RNase activity. Furthermore, phosphatidylinositol (3,4,5) phosphate (PI(3,4,5)P3 ) 5-phosphatase-2 (INPPL1) is a direct target of miR-2137, which controls PI(3,4,5)P3 levels in macrophages. The modulation of cellular PI(3,4,5)P3 /PIP2 ratio and anabolic mTOR signaling by the IRE1-induced miR-2137 demonstrates how the ER can provide a critical input into cell growth decisions.

| S-EPMC7726810 | biostudies-literature

Inositol requiring enzyme 1? augments angiogenesis for diabetic wound healing

Project description:The microarray analysis is to investigate the different expression profile of microRNAs in bone marrow-derived progenitor cells from type 2 diabetic mice and healthy control mice. microRNA expression profiles were compared between bone marrow-derived progenitor cells from either type 2 diabetic db/db mice or their in-colony control litter db/+ mice. Total RNA was extracted from bone marrow-derived progenitor cells from either type 2 diabetic db/db mice (Jackson lab, # 000642) or their in-colony control litter db/+ mice. N=3 per group.

2015-09-02 | E-GEOD-72616 | biostudies-arrayexpress

Inositol requiring enzyme 1α augments angiogenesis for diabetic wound healing

2015-09-02 | GSE72616 | GEO

Inositol-Requiring Enzyme 1-Dependent Activation of AMPK Promotes Brucella abortus Intracellular Growth.

Project description:UnlabelledAMP-activated protein kinase (AMPK) is a serine/threonine kinase that is well conserved during evolution. AMPK activation inhibits production of reactive oxygen species (ROS) in cells via suppression of NADPH oxidase. However, the role of AMPK during the process of Brucella infection remains unknown. Our data demonstrate that B. abortus infection induces AMPK activation in HeLa cells in a time-dependent manner. The known AMPK kinases LKB1, CAMKKβ, and TAK1 are not required for the activation of AMPK by B. abortus infection. Instead, this activation is dependent on the RNase activity of inositol-requiring enzyme 1 (IRE1). Moreover, we also found that B. abortus infection-induced IRE1-dependent activation of AMPK promotes B. abortus intracellular growth with peritoneal macrophages via suppression of NADPH-derived ROS production.ImportancePrevious studies showed that B. abortus infection does not promote any oxidative burst regulated by NADPH oxidase. However, the underlying mechanism remains elusive. We report for the first time that AMPK activation caused by B. abortus infection plays important role in NADPH oxidase-derived ROS production.

| S-EPMC4772604 | biostudies-literature

PKA phosphorylation couples hepatic inositol-requiring enzyme 1alpha to glucagon signaling in glucose metabolism.

Project description:The endoplasmic reticulum (ER)-resident protein kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1) is activated through transautophosphorylation in response to protein folding overload in the ER lumen and maintains ER homeostasis by triggering a key branch of the unfolded protein response. Here we show that mammalian IRE1? in liver cells is also phosphorylated by a kinase other than itself in response to metabolic stimuli. Glucagon-stimulated protein kinase PKA, which in turn phosphorylated IRE1? at Ser(724), a highly conserved site within the kinase activation domain. Blocking Ser(724) phosphorylation impaired the ability of IRE1? to augment the up-regulation by glucagon signaling of the expression of gluconeogenic genes. Moreover, hepatic IRE1? was highly phosphorylated at Ser(724) by PKA in mice with obesity, and silencing hepatic IRE1? markedly reduced hyperglycemia and glucose intolerance. Hence, these results suggest that IRE1? integrates signals from both the ER lumen and the cytoplasm in the liver and is coupled to the glucagon signaling in the regulation of glucose metabolism.

| S-EPMC3179066 | biostudies-literature

Binding Analysis of the Inositol-Requiring Enzyme 1 Kinase Domain.

Project description:Inositol-requiring enzyme 1 (IRE1) is an orchestrator of the unfolded protein response (UPR), the cellular response to endoplasmic reticulum (ER) stress that plays a crucial role in tumor development. IRE1 signaling is the most evolutionary conserved branch of the UPR. Under ER stress, the IRE1 luminal domain undergoes a conformational change to multimerize, resulting in trans-autophosphorylation and activation of the cytosolic kinase and endoribonuclease domain. Adenosine triphosphate-competitive inhibitors that bind to the IRE1 kinase site can modulate the activity of the RNase domain through an allosteric relationship between the IRE1 kinase and RNase domains. The current study aims at the investigation of available structural data of the IRE1 kinase domain and provides insights into the design of novel kinase inhibitors. To this end, a detailed analysis of IRE1 kinase active site and investigation of suitable structures for virtual screening studies were performed. The results indicate in silico target fishing as an appropriate strategy for the identification of novel IRE1 kinase binders, further validating the robustness of the in silico protocol. Importantly, the study highlights the kinase-inhibiting RNase attenuator (KIRA)-bound protein data bank 4U6R structure as the best protein structure to perform virtual screening to develop diverse and more potent KIRA-like IRE1 kinase inhibitors that are capable of allosterically affecting the RNase activity.

| S-EPMC6217623 | biostudies-literature

Inositol Requiring Enzyme (IRE), a multiplayer in sensing endoplasmic reticulum stress.

Project description:The endoplasmic reticulum (ER) can sense a wide variety of external and internal perturbations and responds by mounting stress coping responses, such as the unfolded protein response (UPR). The UPR is composed of three stress sensors, namely IRE1α, PERK, and ATF6 that are activated to re-establish ER homeostasis. IRE1α represents the most ancient branch of the UPR affecting many cellular processes in plant and animal cells. IRE1α is a type I transmembrane protein with kinase/nuclease activities in response to ER stress. Both the ER luminal and cytosolic IRE1α interactomes have been identified revealing a multifunctional role of the ER stress sensor. IRE1α is also associated with organellar membrane contacts to promote rapid communication between intracellular organelles under stress conditions.

| S-EPMC8765250 | biostudies-literature

Inositol-Requiring Enzyme 1 Facilitates Diabetic Wound Healing Through Modulating MicroRNAs.

Project description:Diabetic skin ulcers represent a challenging clinical problem with mechanisms not fully understood. In this study, we investigated the role and mechanism for the primary unfolded protein response (UPR) transducer inositol-requiring enzyme 1 (IRE1α) in diabetic wound healing. Bone marrow-derived progenitor cells (BMPCs) were isolated from adult male type 2 diabetic and their littermate control mice. In diabetic BMPCs, IRE1α protein expression and phosphorylation were repressed. The impaired diabetic BMPC angiogenic function was rescued by adenovirus-mediated expression of IRE1α but not by the RNase-inactive IRE1α or the activated X-box binding protein 1 (XBP1), the canonical IRE1α target. In fact, IRE1α RNase processes a subset of microRNAs (miRs), including miR-466 and miR-200 families, through which IRE1α plays an important role in maintaining BMPC function under the diabetic condition. IRE1α attenuated maturation of miR-466 and miR-200 family members at precursor miR levels through the regulated IRE1α-dependent decay (RIDD) independent of XBP1. IRE1α deficiency in diabetes resulted in a burst of functional miRs from miR-466 and miR-200 families, which directly target and repress the mRNA encoding the angiogenic factor angiopoietin 1 (ANGPT1), leading to decreased ANGPT1 expression and disrupted angiogenesis. Importantly, cell therapies using IRE1α-expressing BMPCs or direct IRE1α gene transfer significantly accelerated cutaneous wound healing in diabetic mice through facilitating angiogenesis. In conclusion, our studies revealed a novel mechanistic basis for rescuing angiogenesis and tissue repair in diabetic wound treatments.

| S-EPMC5204310 | biostudies-literature

Drosophila phosphoinositide-dependent kinase-1 regulates apoptosis and growth via the phosphoinositide 3-kinase-dependent signaling pathway.

Project description:Phosphoinositide-dependent kinase-1 (PDK-1) is a central mediator of the cell signaling between phosphoinositide 3-kinase (PI3K) and various intracellular serine/threonine kinases including Akt/protein kinase B (PKB), p70 S6 kinases, and protein kinase C. Recent studies with cell transfection experiments have implied that PDK-1 may be involved in various cell functions including cell growth and apoptosis. However, despite its pivotal role in cellular signalings, the in vivo functions of PDK-1 in a multicellular system have rarely been investigated. Here, we have isolated Drosophila PDK-1 (dPDK-1) mutants and characterized the in vivo roles of the kinase. Drosophila deficient in the dPDK-1 gene exhibited lethality and an apoptotic phenotype in the embryonic stage. Conversely, overexpression of dPDK-1 increased cell and organ size in a Drosophila PI3K-dependent manner. dPDK-1 not only could activate Drosophila Akt/PKB (Dakt1), but also substitute the in vivo functions of its mammalian ortholog to activate Akt/PKB. This functional interaction between dPDK-1 and Dakt1 was further confirmed through genetic analyses in Drosophila. On the other hand, cAMP-dependent protein kinase, which has been proposed as a possible target of dPDK-1, did not interact with dPDK-1. In conclusion, our findings provide direct evidence that dPDK-1 regulates cell growth and apoptosis during Drosophila development via the PI3K-dependent signaling pathway and demonstrate our Drosophila system to be a powerful tool for elucidating the in vivo functions and targets of PDK-1.

| S-EPMC33436 | biostudies-literature

Multiple autophosphorylations significantly enhance the endoribonuclease activity of human inositol requiring enzyme 1?.

Project description:BackgroundEndoplasmic reticulum stress, caused by the presence of misfolded proteins, activates the stress sensor inositol-requiring enzyme 1? (IRE1?). The resulting increase in IRE1? RNase activity causes sequence-specific cleavage of X-box binding protein 1 (XBP1) mRNA, resulting in upregulation of the unfolded protein response and cellular adaptation to stress. The precise mechanism of human IRE1? activation is currently unclear. The role of IRE1? kinase activity is disputed, as results from the generation of various kinase-inactivating mutations in either yeast or human cells are discordant. Kinase activity can also be made redundant by small molecules which bind the ATP binding site. We set out to uncover a role for IRE1? kinase activity using wild-type cytosolic protein constructs.ResultsWe show that concentration-dependent oligomerisation is sufficient to cause IRE1? cytosolic domain RNase activity in vitro. We demonstrate a role for the kinase activity by showing that autophosphorylation enhances RNase activity. Inclusion of the IRE1? linker domain in protein constructs allows hyperphosphorylation and further enhancement of RNase activity, highlighting the importance of kinase activity. We show that IRE1? phosphorylation status correlates with an increased propensity to form oligomeric complexes and that forced dimerisation causes great enhancement in RNase activity. In addition we demonstrate that even when IRE1? is forced to dimerise, by a GST-tag, phospho-enhancement of activity is still observed.ConclusionsTaken together these experiments support the hypothesis that phosphorylation is important in modulating IRE1? RNase activity which is achieved by increasing the propensity of IRE1? to dimerise. This work supports the development of IRE1? kinase inhibitors for use in the treatment of secretory cancers.

| S-EPMC3928614 | biostudies-literature

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