scholarly journals Vascular inflammation and endothelial injury in SARS-CoV-2 infection: the overlooked regulatory cascades implicated by the ACE2 gene cluster

QJM ◽  
2020 ◽  
Author(s):  
C L Shovlin ◽  
M P Vizcaychipi
Keyword(s):  
Gene Cluster ◽  
Vascular Inflammation ◽  
Feedback Regulation ◽  
Basic Question ◽  
Negative Feedback Regulation ◽  
Antiviral Therapies ◽  
Regulatory Cascades ◽  
Life Threatening ◽  
Endothelial Homeostasis ◽  
Endothelial Growth Factor

Summary Coronavirus disease 2019 (COVID-19) has presented physicians with an unprecedented number of challenges and mortality. The basic question is why, in contrast to other ‘respiratory’ viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in such multi-systemic, life-threatening complications and a severe pulmonary vasculopathy. It is widely known that SARS-CoV-2 uses membrane-bound angiotensin-converting enzyme 2 (ACE2) as a receptor, resulting in internalization of the complex by the host cell. We discuss the evidence that failure to suppress coronaviral replication within 5 days results in sustained downregulation of ACE2 protein expression and that ACE2 is under negative-feedback regulation. We then expose openly available experimental repository data that demonstrate the gene for ACE2 lies in a novel cluster of inter-regulated genes on the X chromosome including PIR encoding pirin (quercetin 2,3-dioxygenase), and VEGFD encoding the predominantly lung-expressed vascular endothelial growth factor D. The five double-elite enhancer/promoters pairs that are known to be operational, and shared read-through lncRNA transcripts, imply that ongoing SARS-CoV-2 infection will reduce host defences to reactive oxygen species, directly generate superoxide O2·− and H2O2 (a ‘ ROS storm’), and impair pulmonary endothelial homeostasis. Published cellular responses to oxidative stress complete the loop to pathophysiology observed in severe COVID-19. Thus, for patients who fail to rapidly suppress viral replication, the newly appreciated ACE2 co-regulated gene cluster predicts delayed responses that would account for catastrophic deteriorations. We conclude that ACE2 homeostatic drives provide a unified understanding that should help optimize therapeutic approaches during the wait until safe, effective vaccines and antiviral therapies for SARS-CoV-2 are delivered.

scholarly journals Transcriptional Regulator PhlH Modulates 2,4-Diacetylphloroglucinol Biosynthesis in Response to the Biosynthetic Intermediate and End Product

2017 ◽  
Vol 83 (21) ◽  
Author(s):  
Xu Yan ◽  
Rui Yang ◽  
Rui-Xue Zhao ◽  
Jian-Ting Han ◽  
Wen-Juan Jia ◽  
...  
Keyword(s):  
Pseudomonas Fluorescens ◽  
Gene Cluster ◽  
Plant Pathogens ◽  
Feedback Regulation ◽  
Biosynthetic Gene Cluster ◽  
Sequence Motif ◽  
Target Sequence ◽  
Gene Encoding ◽  
Negative Feedback Regulation ◽  
Content Type

ABSTRACT Certain strains of biocontrol bacterium Pseudomonas fluorescens produce the secondary metabolite 2,4-diacetylphloroglucinol (2,4-DAPG) to antagonize soilborne phytopathogens in the rhizosphere. The gene cluster responsible for the biosynthesis of 2,4-DAPG is named phlACBDEFGH and it is still unclear how the pathway-specific regulator phlH within this gene cluster regulates the metabolism of 2,4-DAPG. Here, we found that PhlH in Pseudomonas fluorescens strain 2P24 represses the expression of the phlG gene encoding the 2,4-DAPG hydrolase by binding to a sequence motif overlapping with the −35 site recognized by σ70 factors. Through biochemical screening of PhlH ligands we identified the end product 2,4-DAPG and its biosynthetic intermediate monoacetylphloroglucinol (MAPG), which can act as signaling molecules to modulate the binding of PhlH to the target sequence and activate the expression of phlG. Comparison of 2,4-DAPG production between the ΔphlH, ΔphlG, and ΔphlHG mutants confirmed that phlH and phlG impose negative feedback regulation over 2,4-DAPG biosynthesis. It was further demonstrated that the 2,4-DAPG degradation catalyzed by PhlG plays an insignificant role in 2,4-DAPG tolerance but contributes to bacterial growth advantages under carbon/nitrogen starvation conditions. Taken together, our data suggest that by monitoring and down-tuning in situ levels of 2,4-DAPG, the phlHG genes could dynamically modulate the metabolic loads attributed to 2,4-DAPG production and potentially contribute to rhizosphere adaptation. IMPORTANCE 2,4-DAPG, which is synthesized by biocontrol pseudomonad bacteria, is a broad-spectrum antibiotic against bacteria, fungi, oomycetes, and nematodes and plays an important role in suppressing soilborne plant pathogens. Although most of the genes in the 2,4-DAPG biosynthetic gene cluster (phl) have been characterized, it is still not clear how the pathway-specific regulator phlH is involved in 2,4-DAPG metabolism. This work revealed the role of PhlH in modulating 2,4-DAPG levels by controlling the expression of 2,4-DAPG hydrolase PhlG in response to 2,4-DAPG and MAPG. Since 2,4-DAPG biosynthesis imposes a metabolic burden on biocontrol pseudomonads, it is expected that the fine regulation of phlG by PhlH offers a way to dynamically modulate the metabolic loads attributed to 2,4-DAPG production.

scholarly journals Blood Vessel Patterning on Retinal Astrocytes Requires Endothelial Flt-1 (VEGFR-1)

2019 ◽  
Vol 7 (3) ◽  
pp. 18 ◽  
Author(s):  
John C. Chappell ◽  
Jordan Darden ◽  
Laura Beth Payne ◽  
Kathryn Fink ◽  
Victoria L. Bautch
Keyword(s):  
Feedback Regulation ◽  
Vascular Endothelial ◽  
Vascular Networks ◽  
Cellular Mechanisms ◽  
Negative Feedback Regulation ◽  
Retinal Astrocytes ◽  
Maximum Induction ◽  
Vessel Growth ◽  
Critical Components ◽  
Endothelial Growth Factor

Feedback mechanisms are critical components of many pro-angiogenic signaling pathways that keep vessel growth within a functional range. The Vascular Endothelial Growth Factor-A (VEGF-A) pathway utilizes the decoy VEGF-A receptor Flt-1 to provide negative feedback regulation of VEGF-A signaling. In this study, we investigated how the genetic loss of flt-1 differentially affects the branching complexity of vascular networks in tissues despite similar effects on endothelial sprouting. We selectively ablated flt-1 in the post-natal retina and found that maximum induction of flt-1 loss resulted in alterations in endothelial sprouting and filopodial extension, ultimately yielding hyper-branched networks in the absence of changes in retinal astrocyte architecture. The mosaic deletion of flt-1 revealed that sprouting endothelial cells flanked by flt-1−/− regions of vasculature more extensively associated with underlying astrocytes and exhibited aberrant sprouting, independent of the tip cell genotype. Overall, our data support a model in which tissue patterning features, such as retinal astrocytes, integrate with flt-1-regulated angiogenic molecular and cellular mechanisms to yield optimal vessel patterning for a given tissue.

scholarly journals Modulation of Endosome Function, Vesicle Trafficking and Autophagy by Human Herpesviruses

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 542
Author(s):  
Eduardo I. Tognarelli ◽  
Antonia Reyes ◽  
Nicolás Corrales ◽  
Leandro J. Carreño ◽  
Susan M. Bueno ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Viral Gene ◽  
Barr Virus ◽  
Cellular Processes ◽  
Antiviral Therapies ◽  
Host Determinants ◽  
Viral Particles ◽  
Life Threatening ◽  
Epstein Barr ◽  
Human Herpesviruses

Human herpesviruses are a ubiquitous family of viruses that infect individuals of all ages and are present at a high prevalence worldwide. Herpesviruses are responsible for a broad spectrum of diseases, ranging from skin and mucosal lesions to blindness and life-threatening encephalitis, and some of them, such as Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein–Barr virus (EBV), are known to be oncogenic. Furthermore, recent studies suggest that some herpesviruses may be associated with developing neurodegenerative diseases. These viruses can establish lifelong infections in the host and remain in a latent state with periodic reactivations. To achieve infection and yield new infectious viral particles, these viruses require and interact with molecular host determinants for supporting their replication and spread. Important sets of cellular factors involved in the lifecycle of herpesviruses are those participating in intracellular membrane trafficking pathways, as well as autophagic-based organelle recycling processes. These cellular processes are required by these viruses for cell entry and exit steps. Here, we review and discuss recent findings related to how herpesviruses exploit vesicular trafficking and autophagy components by using both host and viral gene products to promote the import and export of infectious viral particles from and to the extracellular environment. Understanding how herpesviruses modulate autophagy, endolysosomal and secretory pathways, as well as other prominent trafficking vesicles within the cell, could enable the engineering of novel antiviral therapies to treat these viruses and counteract their negative health effects.

scholarly journals The Structure of the PanD/PanZ Protein Complex Reveals Negative Feedback Regulation of Pantothenate Biosynthesis by Coenzyme A

2015 ◽  
Vol 22 (4) ◽  
pp. 492-503 ◽  
Author(s):  
Diana C.F. Monteiro ◽  
Vijay Patel ◽  
Christopher P. Bartlett ◽  
Shingo Nozaki ◽  
Thomas D. Grant ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Protein Complex ◽  
Coenzyme A ◽  
Feedback Regulation ◽  
Negative Feedback Regulation ◽  
Pantothenate Biosynthesis
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