scholarly journals The Hexosamine Biosynthetic Pathway Links Innate Inflammation With Epithelial-Mesenchymal Plasticity in Airway Remodeling

2021 ◽  
Vol 12 ◽  
Author(s):  
Allan R. Brasier ◽  
Dianhua Qiao ◽  
Yingxin Zhao
Keyword(s):  
Transcription Factor ◽  
Growth Factors ◽  
Biosynthetic Pathway ◽  
Nuclear Translocation ◽  
Airway Remodeling ◽  
Metabolic Reprogramming ◽  
Lower Airway ◽  
Epithelial Barrier ◽  
Hexosamine Biosynthetic Pathway ◽  
Factor Module

Disruption of the lower airway epithelial barrier plays a major role in the initiation and progression of chronic lung disease. Here, repetitive environmental insults produced by viral and allergens triggers metabolic adaptations, epithelial-mesenchymal plasticity (EMP) and airway remodeling. Epithelial plasticity disrupts epithelial barrier function, stimulates release of fibroblastic growth factors, and remodels the extracellular matrix (ECM). This review will focus on recent work demonstrating how the hexosamine biosynthetic pathway (HBP) links innate inflammation to airway remodeling. The HBP is a core metabolic pathway of the unfolded protein response (UPR) responsible for protein N-glycosylation, relief of proteotoxic stress and secretion of ECM modifiers. We will overview findings that the IκB kinase (IKK)-NFκB pathway directly activates expression of the SNAI-ZEB1 mesenchymal transcription factor module through regulation of the Bromodomain Containing Protein 4 (BRD4) chromatin modifier. BRD4 mediates transcriptional elongation of SNAI1-ZEB as well as enhancing chromatin accessibility and transcription of fibroblast growth factors, ECM and matrix metalloproteinases (MMPs). In addition, recent exciting findings that IKK cross-talks with the UPR by controlling phosphorylation and nuclear translocation of the autoregulatory XBP1s transcription factor are presented. HBP is required for N glycosylation and secretion of ECM components that play an important signaling role in airway remodeling. This interplay between innate inflammation, metabolic reprogramming and lower airway plasticity expands a population of subepithelial myofibroblasts by secreting fibroblastic growth factors, producing changes in ECM tensile strength, and fibroblast stimulation by MMP binding. Through these actions on myofibroblasts, EMP in lower airway cells produces expansion of the lamina reticularis and promotes airway remodeling. In this manner, metabolic reprogramming by the HBP mediates environmental insult-induced inflammation with remodeling in chronic airway diseases.

scholarly journals Glutamine enhances heat shock protein 70 expression via increased hexosamine biosynthetic pathway activity

2009 ◽  
Vol 297 (6) ◽  
pp. C1509-C1519 ◽  
Author(s):  
Christine R. Hamiel ◽  
Shanti Pinto ◽  
Ann Hau ◽  
Paul E. Wischmeyer
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Western Blotting ◽  
Transcriptional Activation ◽  
Heat Shock Protein 70 ◽  
Biosynthetic Pathway ◽  
Nuclear Translocation ◽  
Hsp70 Expression ◽  
Hexosamine Biosynthetic Pathway ◽  
Cellular Protection

Glutamine (GLN) plays a key role in cellular protection following injury via enhancement of heat shock protein 70 (HSP70). The pathway by which GLN enhances HSP70 is unknown. GLN is a key substrate for the hexosamine biosynthetic pathway (HBP), which has been shown to induce HSP70. We sought to explore the role of the HBP in GLN-mediated HSP70 expression. Both chemical inhibitors and small interfering (si)RNA knockdown of key HBP enzymes were used in mouse embryonic fibroblast cells to determine the effects of the HBP on HSP70 expression. The O-glycosylation, nuclear translocation, and transcriptional activation of heat shock factor-1 (HSF-1) and Sp1 were evaluated using immunoprecipitation, Western blotting, and luciferase assays. HSP70 expression levels were evaluated via ELISA and Western blotting. GLN augmented HBP activity before and after heat stress (HS). Chemical inhibition of HBP enzymes reduced GLN-mediated HSP70 expression. Specific siRNA targeting of the key HBP enzyme UDP- N-acetylglucosamine (GlcNAc): polypeptide- O-β-acetylglucosaminyltransferase (OGT) blocked GLN-mediated HSP70 expression and attenuated GLN-mediated cellular protection post-HS. Chemical and siRNA attenuation of the HBP blocked GLN-induced nuclear translocation of Sp1 and HSF-1, which are key to maximal HSP70 expression. Finally, immunoprecipitation revealed HSF-1 was O-glycosylated, and GLN enhanced this effect. These results suggest that metabolism of GLN via the HBP enhances HSP70 expression. This effect appears to be mediated via O-glycosylation, nuclear translocation, and transcriptional activation of Sp1 and HSF-1. This is an important mechanistic description of a pathway that appears responsible for GLN-mediated HSP70 expression.

scholarly journals Transcription factor EB and TFE3: new metabolic coordinators mediating adaptive responses to exercise in skeletal muscle?

2020 ◽  
Vol 319 (4) ◽  
pp. E763-E768 ◽  
Author(s):  
Greg Robert Markby ◽  
Kei Sakamoto
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Spatial Organization ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Contractile Activity ◽  
Metabolic Reprogramming ◽  
Peroxisome Proliferator ◽  
Adaptive Responses ◽  
Transcription Factor Eb

In response to the increased energy demands of contractions, skeletal muscle adapts remarkably well through acutely regulating metabolic pathways to maintain energy balance and in the longer term by regulating metabolic reprogramming, such as remodeling and expanding the mitochondrial network. This long-term adaptive response involves modulation of gene expression at least partly through the regulation of specific transcription factors and transcriptional coactivators. The AMPK-peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) pathway has long been known to orchestrate contraction-mediated adaptive responses, although AMPK- and PGC1α-independent pathways have also been proposed. Transcription factor EB (TFEB) and TFE3, known as important regulators of lysosomal biogenesis and autophagic processes, have emerged as new metabolic coordinators. The activity of TFEB/TFE3 is regulated through posttranslational modifications (i.e., phosphorylation) and spatial organization. Under nutrient and energy stress, TFEB and TFE3 are dephosphorylated and translocate to the nucleus, where they activate transcription of their target genes. It has recently been reported that exercise promotes nuclear translocation and activation of TFEB/TFE3 in mouse skeletal muscle through the Ca2+-stimulated protein phosphatase calcineurin. Skeletal muscle-specific ablation of TFEB exhibits impaired glucose homeostasis and mitochondrial biogenesis with reduced metabolic flexibility during exercise, and global TFE3 depletion results in diminished endurance and abolished exercise-induced metabolic benefits. Transcriptomic analysis of the muscle-specific TFEB-null mice has demonstrated that TFEB regulates the expression of genes involved in glucose metabolism and mitochondrial homeostasis. This review aims to summarize and discuss emerging roles for TFEB/TFE3 in metabolic and adaptive responses to exercise and contractile activity in skeletal muscle.

scholarly journals Metabolic reprogramming of murine cardiomyocytes during autophagy requires the extracellular nutrient sensor decorin

2018 ◽  
Vol 293 (43) ◽  
pp. 16940-16950 ◽  
Author(s):  
Maria A. Gubbiotti ◽  
Erin Seifert ◽  
Ulrich Rodeck ◽  
Jan B. Hoek ◽  
Renato V. Iozzo
Keyword(s):  
Extracellular Matrix ◽  
Biosynthetic Pathway ◽  
Essential Role ◽  
Cardiac Tissue ◽  
Tissue Homeostasis ◽  
Metabolic Reprogramming ◽  
Hexosamine Biosynthetic Pathway ◽  
Reduced Ejection Fraction ◽  
Health And Disease

The extracellular matrix is a master regulator of tissue homeostasis in health and disease. Here we examined how the small, leucine-rich, extracellular matrix proteoglycan decorin regulates cardiomyocyte metabolism during fasting in vivo. First, we validated in Dcn−/− mice that decorin plays an essential role in autophagy induced by fasting. High-throughput metabolomics analyses of cardiac tissue in Dcn−/− mice subjected to fasting revealed striking differences in the hexosamine biosynthetic pathway resulting in aberrant cardiac O-β-N-acetylglycosylation as compared with WT mice. Functionally, Dcn−/− mice maintained cardiac function at a level comparable with nonfasted animals whereas fasted WT mice showed reduced ejection fraction. Collectively, our results suggest that reduced sensing of nutrient deprivation in the absence of decorin preempts functional adjustments of cardiac output associated with metabolic reprogramming.

New insights into heparan sulphate biosynthesis from the study of mutant mice

2002 ◽  
Vol 69 ◽  
pp. 47-57 ◽  
Author(s):  
Catherine L. R. Merry ◽  
John T. Gallagher
Keyword(s):  
Growth Factors ◽  
Biosynthetic Pathway ◽  
Heparan Sulphate ◽  
Mutant Mice ◽  
Gene Products ◽  
Multiple Gene ◽  
Adhesion Proteins ◽  
Ligand Interactions

Heparan sulphate (HS) is an essential co-receptor for a number of growth factors, morphogens and adhesion proteins. The biosynthetic modifications involved in the generation of a mature HS chain may determine the strength and outcome of HS–ligand interactions. These modifications are catalysed by a complex family of enzymes, some of which occur as multiple gene products. Various mutant mice have now been generated, which lack the function of isolated components of the HS biosynthetic pathway. In this discussion, we outline the key findings of these studies, and use them to put into context our own work concerning the structure of the HS generated by the Hs2st-/- mice.

scholarly journals A combinatorial action of GmMYB176 and GmbZIP5 controls isoflavonoid biosynthesis in soybean (Glycine max)

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Arun Kumaran Anguraj Vadivel ◽  
Tim McDowell ◽  
Justin B. Renaud ◽  
Sangeeta Dhaubhadel
Keyword(s):  
Transcription Factor ◽  
Hairy Roots ◽  
Defense Mechanisms ◽  
Biosynthetic Pathway ◽  
Bzip Transcription Factor ◽  
Myb Transcription Factor ◽  
In Planta ◽  
Rnai Silencing ◽  
Protein Protein Interaction ◽  
Soybean Roots

AbstractGmMYB176 is an R1 MYB transcription factor that regulates multiple genes in the isoflavonoid biosynthetic pathway, thereby affecting their levels in soybean roots. While GmMYB176 is important for isoflavonoid synthesis, it is not sufficient for the function and requires additional cofactor(s). The aim of this study was to identify the GmMYB176 interactome for the regulation of isoflavonoid biosynthesis in soybean. Here, we demonstrate that a bZIP transcription factor GmbZIP5 co-immunoprecipitates with GmMYB176 and shows protein–protein interaction in planta. RNAi silencing of GmbZIP5 reduced the isoflavonoid level in soybean hairy roots. Furthermore, co-overexpression of GmMYB176 and GmbZIP5 enhanced the level of multiple isoflavonoid phytoallexins including glyceollin, isowighteone and a unique O-methylhydroxy isoflavone in soybean hairy roots. These findings could be utilized to develop biotechnological strategies to manipulate the metabolite levels either to enhance plant defense mechanisms or for human health benefits in soybean or other economically important crops.

scholarly journals The Hexosamine Biosynthetic Pathway as a Therapeutic Target after Cartilage Trauma: Modification of Chondrocyte Survival and Metabolism by Glucosamine Derivatives and PUGNAc in an Ex Vivo Model

2021 ◽  
Vol 22 (14) ◽  
pp. 7247
Author(s):  
Jana Riegger ◽  
Julia Baumert ◽  
Frank Zaucke ◽  
Rolf E. Brenner
Keyword(s):  
Biosynthetic Pathway ◽  
Ex Vivo ◽  
Type Ii Collagen ◽  
Cartilage Explants ◽  
Uridine Diphosphate ◽  
Cell Protection ◽  
Ex Vivo Model ◽  
Human Cartilage ◽  
Hexosamine Biosynthetic Pathway ◽  
Cellular Processes

The hexosamine biosynthetic pathway (HBP) is essential for the production of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the building block of glycosaminoglycans, thus playing a crucial role in cartilage anabolism. Although O-GlcNAcylation represents a protective regulatory mechanism in cellular processes, it has been associated with degenerative diseases, including osteoarthritis (OA). The present study focuses on HBP-related processes as potential therapeutic targets after cartilage trauma. Human cartilage explants were traumatized and treated with GlcNAc or glucosamine sulfate (GS); PUGNAc, an inhibitor of O-GlcNAcase; or azaserine (AZA), an inhibitor of GFAT-1. After 7 days, cell viability and gene expression analysis of anabolic and catabolic markers, as well as HBP-related enzymes, were performed. Moreover, expression of catabolic enzymes and type II collagen (COL2) biosynthesis were determined. Proteoglycan content was assessed after 14 days. Cartilage trauma led to a dysbalanced expression of different HBP-related enzymes, comparable to the situation in highly degenerated tissue. While GlcNAc and PUGNAc resulted in significant cell protection after trauma, only PUGNAc increased COL2 biosynthesis. Moreover, PUGNAc and both glucosamine derivatives had anti-catabolic effects. In contrast, AZA increased catabolic processes. Overall, “fueling” the HBP by means of glucosamine derivatives or inhibition of deglycosylation turned out as cells and chondroprotectives after cartilage trauma.

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