☆ 4.7 Review

ACE2 in chronic disease and COVID-19: gene regulation and post-translational modification

JOURNAL OF BIOMEDICAL SCIENCE (2023)

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CDK4/6 inhibitor palbociclib promotes SARS-CoV-2 cell entry by down-regulating SKP2 dependent ACE2 degradation

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Nedd4-2 up-regulation is associated with ACE2 ubiquitination in hypertension

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Summary: This study aimed to identify E3 ubiquitin ligases associated with ACE2 ubiquitination in neurogenic hypertension and establish their clinical relevance. By combining bioinformatics and proteomics, the researchers were able to identify Nedd4-2 as the first E3 ubiquitin ligase involved in ACE2 ubiquitination in Ang-II-mediated hypertension. They also demonstrated the important role of ACE2 in GABAergic neurons in maintaining inhibitory tone and regulating pre-sympathetic activity. These findings provide a new understanding of the development of neurogenic hypertension and potential therapeutic strategies. Rating: 9/10.

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P38 MAPK activated ADAM17 mediates ACE2 shedding and promotes cardiac remodeling and heart failure after myocardial infarction

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Summary: Heart failure (HF) after myocardial infarction (MI) is a prevalent disease with a poor prognosis. ADAM17 expression is increased in patients with acute MI, but its functional role in post-MI HF remains unclear. This study found that high levels of ADAM17 predict a higher incidence of post-MI HF, poorer cardiac function, and higher mortality. Animal and in vitro studies further demonstrated that ADAM17 promotes the occurrence and progression of post-MI HF.

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Joanna Szostak et al.

Summary: Diabetic nephropathy is a common and severe complication of diabetes mellitus, and it affects one in every five diabetic patients. The exact pathogenesis is still unclear, but reactive oxygen species and the renin-angiotensin-aldosterone system are known to be involved. Recent research shows significant changes in miRNA expression in diabetic nephropathy patients. This review focuses on the role of miRNA in various pathways and its potential as biomarkers and therapeutic targets.

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GSK3326595 is a promising drug to prevent SARS-CoV-2 Omicron and other variants infection by inhibiting ACE2-R671 di-methylation

Zhongwei Li et al.

Summary: The study reveals that PRMT5 catalyzes the methylation of ACE2, which plays a crucial role in the binding of SARS-CoV-2. The specific inhibitor GSK3326595 can reduce ACE2 binding with the virus, indicating its potential as a promising candidate for inhibiting SARS-CoV-2 infection.

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Article Biochemistry & Molecular Biology

DYRK1A promotes viral entry of highly pathogenic human coronaviruses in a kinase-independent manner

Madison S. Strine et al.

Summary: Identifying host genes essential for SARS-CoV-2 can reveal potential drug targets and advance our understanding of COVID-19. This study demonstrates that DYRK1A regulates the expression of ACE2 and DPP4, influencing the entry of multiple highly pathogenic human coronaviruses. The findings have significant implications for the development of therapeutic strategies against coronavirus infections.

PLOS BIOLOGY (2023)

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Review Cell Biology

Proteoglycans: a common portal for SARS-CoV-2 and extracellular vesicle uptake

Myriam Cerezo-Magana et al.

Summary: As structural components of the glycocalyx, heparan sulfate proteoglycans (HSPGs) play multiple roles in cell signaling cascades and act as endocytosis receptors for particle structures including lipoproteins, extracellular vesicles, and enveloped viruses like SARS-CoV-2. However, HSPGs are still not extensively studied due to their diversity and complex regulation. Recent studies have focused on HSPGs as receptors for internalizing extracellular vesicles and SARS-CoV-2 particles and have highlighted similarities in their biophysical and structural characteristics. Understanding these similarities, such as their biogenesis, size, and lipid composition, may help explain their reliance on HSPGs for efficient attachment and uptake on the cell surface. Additionally, the complex composition of extracellular vesicles and viral mechanisms that enhance infectivity complicate therapeutic strategies targeting their uptake.

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Inhibiting the Deubiquitinase UCHL1 Reduces SARS-CoV-2 Viral Uptake by ACE2

Joseph S. Bednash et al.

Summary: SARS-CoV-2 enters host cells through the interaction of its spike protein with ACE2. The research discovered that UCHL1 enzyme can regulate ACE2 protein levels, making it a potential therapeutic target for developing small molecule drugs to treat COVID-19.

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Enhanced SARS-CoV-2 entry via UPR-dependent AMPK-related kinase NUAK2

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Summary: SARS-CoV-2 infection causes changes in the endoplasmic reticulum and activates the IRE1a pathway, which regulates the host-dependency factor NUAK2. NUAK2 is involved in viral entry and spread by modulating the cell surface levels of viral receptors and viral trafficking.

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Transcriptional regulation and small compound targeting of ACE2 in lung epithelial cells

Li-jun Liang et al.

Summary: In this study, the researchers evaluated the transcription factors that regulate ACE2 expression and identified 24 potential regulators, with Stat3 being the most significant one. They also found that a compound called 6-OAP could effectively inhibit ACE2 expression and reduce IL-6 production. Moreover, 6-OAP was found to inhibit the entry of SARS-CoV-2 into target cells.

ACTA PHARMACOLOGICA SINICA (2022)

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ADAM10 and ADAM17 promote SARS-CoV-2 cell entry and spike protein-mediated lung cell fusion

Georg Jocher et al.

Summary: Host metalloproteases ADAM10 and ADAM17 play important roles in facilitating SARS-CoV-2 cell entry and syncytia formation in lung cells, and are potential targets for antiviral drug development.

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Genome-wide CRISPR screens identify GATA6 as a proviral host factor for SARS-CoV-2 via modulation of ACE2

Ma'ayan Israeli et al.

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NATURE COMMUNICATIONS (2022)

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Article Microbiology

Identification of cell type specific ACE2 modifiers by CRISPR screening

Emily W. Sherman et al.

Summary: This study identified genes that regulate the surface abundance of ACE2, the receptor for SARS-CoV-2, in different cell lines. The findings highlight the cell type specificity of ACE2 regulatory networks and suggest potential targets for therapeutic development.

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SARS-CoV-2 spike protein enhances MAP4K3/GLK-induced ACE2 stability in COVID-19

Huai-Chia Chuang et al.

Summary: Overexpression of GLK leads to stabilization of ACE2, promoting the invasion and infection of SARS-CoV-2. These findings may help to explain the pathogenesis of COVID-19.

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Signalling mechanisms and cellular functions of SUMO

Alfred C. O. Vertegaal

Summary: Sumoylation is an essential post-translational modification that regulates many nuclear processes. Recent studies have revealed its roles in liquid-liquid phase separation, immunity, pluripotency, and disease, offering new therapeutic opportunities.

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ACE2 N-glycosylation modulates interactions with SARS-CoV-2 spike protein in a site-specific manner

Ayana Isobe et al.

Summary: This study investigates the importance of ACE2 glycosylation in the interaction between SARS-CoV-2 virus and ACE2 receptor. The findings demonstrate that the deletion of glycosylation sites results in significant changes in the interaction with spike protein and is consistent across viral variants.

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Yi Lu et al.

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Suppression of ACE2 SUMOylation protects against SARS-CoV-2 infection through TOLLIP-mediated selective autophagy

Shouheng Jin et al.

Summary: The study found that SARS-CoV-2 infection can modulate the SUMOylation of ACE2, a host receptor used for cell entry, leading to its stabilization and reduced degradation. By inhibiting ACE2 SUMOylation, it is possible to block SARS-CoV-2 infection.

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Zheng Ma et al.

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Molecules in pathogenesis: angiotensin converting enzyme 2 (ACE2)

Owen Wiese et al.

Summary: ACE2 is a key enzyme that plays a central role in diseases affecting multiple organ systems, especially in COVID-19. Its function includes converting angiotensin to counteract the vasoconstrictive effects of the system and exerting a protective effect in the lung and kidney.

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Ashley Kieran Clift et al.

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Individuals with Down syndrome hospitalized with COVID-19 have more severe disease

Louise Malle et al.

Summary: This study analyzed individuals with Down syndrome who were hospitalized with COVID-19 in New York City and found that they were on average ten years younger than non-DS patients and had more severe disease, particularly with an increased incidence of sepsis and mechanical ventilation. Special care should be considered for both the prevention and treatment of COVID-19 in these patients.

GENETICS IN MEDICINE (2021)

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Review Biotechnology & Applied Microbiology

Epigenetic regulation of ACE2, the receptor of the SARS-CoV-2 virus

Tasnim H. Beacon et al.

Summary: ACE2 is the receptor for three coronaviruses and involved in regulating the renin-angiotensin system and blood pressure, as well as various signaling pathways. Its expression is regulated by two promoters, with tissue-specific differences, and is highest in the small intestine, kidney, and heart.

GENOME (2021)

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Review Biochemistry & Molecular Biology

The Two-Way Switch Role of ACE2 in the Treatment of Novel Coronavirus Pneumonia and Underlying Comorbidities

Xiao Cong Pang et al.

Summary: ACE2, as the functional receptor for SARS-CoV-2, plays a crucial role in the infection process, making it an important target for drug intervention in the treatment of COVID-19. Blocking specific binding sites on ACE2 could potentially prevent viral transmission, and recombinant ACE2 protein may serve as a potential treatment option for acute severe lung failure caused by SARS-CoV-2 infection.

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A novel ACE2 isoform is expressed in human respiratory epithelia and is upregulated in response to interferons and RNA respiratory virus infection

Cornelia Blume et al.

Summary: A novel short isoform of ACE2, substantially upregulated in response to interferon stimulation and rhinovirus infection, was identified in airway epithelial cells, the main site of SARS-CoV-2 infection. This short isoform lacks high-affinity binding sites for the SARS-CoV-2 spike protein, suggesting it may not directly contribute to host susceptibility to SARS-CoV-2 infection.

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Network analysis of Down syndrome and SARS-CoV-2 identifies risk and protective factors for COVID-19

Ilario De Toma et al.

Summary: Individuals with Down syndrome may be more susceptible to SARS-CoV-2 infection due to specific genetic factors, but also exhibit enhanced anti-viral signaling that can inhibit viral replication. However, in the later stages of infection, the prognosis for individuals with Down syndrome may worsen as upregulation of inflammatory genes could lead to a cytokine storm typical of COVID-19.

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Annkatrin Wagner

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Biomechanical characterization of SARS-CoV-2 spike RBD and human ACE2 protein-protein interaction

Wenpeng Cao et al.

Summary: This study utilizes single-molecule force spectroscopy and molecular dynamics simulations to quantify the interactions between SARS-CoV-2 or SARS-CoV-1 RBD and ACE2, revealing that the N-linked glycan interaction plays a crucial role in the binding difference between the two viruses. The study uncovers the mechanism behind ACE2 binding disparity and provides insights for developing new strategies to inhibit SARS-CoV-2 entry.

BIOPHYSICAL JOURNAL (2021)

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Soluble ACE2-mediated cell entry of SARS-CoV-2 via interaction with proteins related to the renin-angiotensin system

Man Lung Yeung et al.

Summary: Research has identified the crucial role of human host factors and sACE2 protein in virus dependency factors, cell entry, and other aspects of SARS-CoV-2 infection, shedding light on the pathogenesis of COVID-19 and potential treatment strategies.

CELL (2021)

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Altered Intestinal ACE2 Levels Are Associated With Inflammation, Severe Disease, and Response to Anti-Cytokine Therapy in Inflammatory Bowel Disease

Alka A. Potdar et al.

Summary: The study identified differences in intestinal ACE2 expression levels in patients with Crohn's disease and ulcerative colitis, associated with inflammation and disease severity. Treatment with anti-cytokine therapy restored ACE2 expression, potentially impacting outcomes of severe acute respiratory syndrome coronavirus 2 infection.

GASTROENTEROLOGY (2021)

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Specific Susceptibility to COVID-19 in Adults with Down Syndrome

Tomer Illouz et al.

Summary: Individuals with Down Syndrome (DS) are at higher risk of contracting COVID-19, especially those with Alzheimer's disease (AD). Urgent measures need to be taken to protect these patients, while global health systems should focus on interventions for prevention and control.

NEUROMOLECULAR MEDICINE (2021)

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Degradation of SARS-CoV-2 receptor ACE2 by the E3 ubiquitin ligase Skp2 in lung epithelial cells

Guizhen Wang et al.

Summary: The observation of a lower proportion of smokers among hospitalized COVID-19 patients has led to a study showing that tobacco carcinogens reduce ACE2 levels and inhibit SARS-CoV-2 infection, highlighting the importance of discouraging smoking and implementing cessation plans for smokers during the pandemic.

FRONTIERS OF MEDICINE (2021)

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Spotlight on USP4: Structure, Function, and Regulation

Binbin Hu et al.

Summary: USP4 is a critical deubiquitinating enzyme involved in regulating the balance of protein synthesis and degradation, sharing a common domain organization with its paralogs USP11 and USP15. It plays a crucial role in normal physiological conditions and aberrant expression or activity of USP4 is implicated in the progression of various pathologies, especially cancers. Effective therapeutic interventions targeting USP4 are important for potential treatment strategies.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2021)

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Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor

Tuemay Capraz et al.

Summary: The interaction between the Spike protein of SARS-CoV-2 and ACE2 on host cells is crucial for viral entry, with glycosylation playing a critical role. Engineering ACE2 glycosylation can enhance virus neutralization without affecting protein stability or activity. Removing all N-glycans from recombinant soluble human ACE2 can create a superior decoy receptor for effective COVID-19 treatment.

ELIFE (2021)

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Chitinase 3-like-1 is a therapeutic target that mediates the effects of aging in COVID-19

Suchitra Kamle et al.

Summary: CHI3L1 is induced in elderly individuals and patients with comorbid diseases, playing a significant role in stimulating ACE2 and SPP during SC2 infection, and its levels correlate with COVID-19 severity.

JCI INSIGHT (2021)

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Article Multidisciplinary Sciences

Dual nature of human ACE2 glycosylation in binding to SARS-CoV-2 spike

Ahmad Reza Mehdipour et al.

Summary: Glycosylation of the human ACE2 receptor plays a substantial role in the binding of the SARS-CoV-2 virus. Glycans at the N90 and N322 sites have opposite effects on spike protein binding, with the N90 glycan interfering with binding and the N322 glycan strengthening the complex. Additionally, the N322 glycan binds to a conserved region of the spike protein that has been identified as a cryptic epitope for a neutralizing antibody, showing potential for the development of targeted neutralizing antibodies and fusion inhibitors against SARS-CoV-2.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2021)

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Elabela prevents angiotensin II-induced apoptosis and inflammation in rat aortic adventitial fibroblasts via the activation of FGF21-ACE2 signaling

Juan-Juan Song et al.

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SPOP and OTUD7A Control EWS-FLI1 Protein Stability to Govern Ewing Sarcoma Growth

Siyuan Su et al.

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JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION (2020)

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Protective regulation of the ACE2/ACE gene expression by estrogen in human atrial tissue from elderly men

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The sirtuin 6 prevents angiotensin II-mediated myocardial fibrosis and injury by targeting AMPK-ACE2 signaling

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SIRT6 protects cardiomyocytes against ischemia/reperfusion injury by augmenting FoxO3α-dependent antioxidant defense mechanisms

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Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1-FoxM1 complex

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GLK/MAP4K3 overexpression associates with recurrence risk for non-small cell lung cancer

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Chitinase 3-like-1 Regulates Both Visceral Fat Accumulation and Asthma-like Th2 Inflammation

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Genetic variation in chitinase 3-like 1 (CHI3L1) contributes to asthma severity and airway expression of YKL-40

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Angiotensin II-regulated microRNA 483-3p directly targets multiple components of the renin-angiotensin system

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TMPRSS2 and ADAM17 Cleave ACE2 Differentially and Only Proteolysis by TMPRSS2 Augments Entry Driven by the Severe Acute Respiratory Syndrome Coronavirus Spike Protein

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Expression and function of the ACE2/angiotensin(1-7)/Mas axis in osteosarcoma cell lines U-2 OS and MNNG-HOS

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Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury

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Acetylation of histone H3 at lysine 64 regulates nucleosome dynamics and facilitates transcription

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IFITM-Family Proteins: The Cell's First Line of Antiviral Defense

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ANNUAL REVIEW OF VIROLOGY, VOL 1 (2014)

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Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice

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The transcription factor HNF1α induces expression of angiotensin-converting enzyme 2 (ACE2) in pancreatic islets from evolutionarily conserved promoter motifs

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High urinary ACE2 concentrations are associated with severity of glucose intolerance and microalbuminuria

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Interaction between TGF-β and ACE2-Ang-(1-7)-Mas pathway in high glucose-cultured NRK-52E cells

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Suppression of inflammation and acute lung injury by Miz1 via repression of C/EBP-δ

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Angiotensin-converting enzyme 2 attenuates the metastasis of non-small cell lung cancer through inhibition of epithelial-mesenchymal transition

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Rosiglitazone Treatment of Type 2 Diabetic db/db Mice Attenuates Urinary Albumin and Angiotensin Converting Enzyme 2 Excretion

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Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

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The kinase GLK controls autoimmunity and NF-κB signaling by activating the kinase PKC-θ in T cells

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Angiotensin I-Converting Enzyme Type 2 (ACE2) Gene Therapy Improves Glycemic Control in Diabetic Mice

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Physiological Genomics Identifies Estrogen-Related Receptor alpha as a Regulator of Renal Sodium and Potassium Homeostasis and the Renin-Angiotensin Pathway

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Chromatin regulation by Brg1 underlies heart muscle development and disease

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Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17β-oestradiol-dependent and sex chromosome-independent

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Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia

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Role of HIF-1α in the regulation ACE and ACE2 expression in hypoxic human pulmonary artery smooth muscle cells

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Therapeutic Strategies in the Treatment of Diabetic Nephropathy - a Translational Medicine Approach

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CURRENT MEDICINAL CHEMISTRY (2009)

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PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure

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CURRENT OPINION IN LIPIDOLOGY (2009)

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High serum YKL-40 concentration is associated with cardiovascular and all-cause mortality in patients with stable coronary artery disease

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Structures of SPOP-Substrate Complexes: Insights into Molecular Architectures of BTB-Cul3 Ubiquitin Ligases

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AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity

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Breaking the chains: structure and function of the deubiquitinases

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Review Endocrinology & Metabolism

Caloric restriction, SIRT1 and longevity

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TRENDS IN ENDOCRINOLOGY AND METABOLISM (2009)

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Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway

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Targeting the MDM2-p53 interaction for cancer therapy

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Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt

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SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1 - Possible role in AMP-activated protein kinase activation

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Decreased glomerular and tubular expression of ACE2 in patients with type 2 diabetes and kidney disease

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KIDNEY INTERNATIONAL (2008)

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Renal ACE and ACE2 expression in early diabetic rats

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Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function

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NEW ENGLAND JOURNAL OF MEDICINE (2008)

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Glomerular renin angiotensin system in streptozotocin diabetic and Zucker diabetic fatty rats

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TRANSLATIONAL RESEARCH (2008)

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A chitinase-like protein in the lung and circulation of patients with severe asthma

Geoffrey L. Chupp et al.

NEW ENGLAND JOURNAL OF MEDICINE (2007)

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Dyrk1A overexpression in immortalized hippocampal cells produces the neuropathological features of Down syndrome

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MOLECULAR AND CELLULAR NEUROSCIENCE (2007)

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Glomerular localization and expression of angiotensin-converting enzyme 2 and angiotensin-converting enzyme: Implications for albuminuria in diabetes

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JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY (2006)

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ACE and ACE2 activity in diabetic mice

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Identification of target genes of the transcription factor HNF1β and HNF1α in a human embryonic kidney cell line

S Senkel et al.

BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION (2005)

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Tumor necrosis factor-α convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2)

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Histone H3 lysine 9 methylation and HP1γ are associated with transcription elongation through mammalian chromatin

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Improved islet morphology after blockade of the renin-angiotensin system in the ZDF rat

C Tikellis et al.

DIABETES (2004)

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Article Peripheral Vascular Disease

Increased ACE 2 and decreased ACE protein in renal tubules from diabetic mice - A renoprotective combination?

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Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

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Review Endocrinology & Metabolism

Regulation of pancreatic β-cell function by the HNF transcription network:: Lessons from maturity-onset diabetes of the young (MODY)

K Yamagata

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Characterization of renal angiotensin-converting enzyme 2 in diabetic nephropathy

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TRANSFAC (R): transcriptional regulation, from patterns to profiles

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A human homolog of angiotensin-converting enzyme - Cloning and functional expression as a captopril-insensitive carboxypeptidase

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