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Essays Biochem ; 65(6): 1025-1038, 2021 12 17.
Article in English | MEDLINE | ID: covidwho-1334002


COVID-19 symptoms and mortality are largely due to its devastating effects in the lungs. The disease is caused by the SARS (Severe Acute Respiratory Syndrome)-CoV-2 coronavirus, which requires host cell proteins such as ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane serine protease 2) for infection of lung epithelia. The expression and function of the steroid hormone receptor family is important in many aspects that impact on COVID-19 effects in the lung - notably lung development and function, the immune system, and expression of TMPRSS2 and ACE2. This review provides a brief summary of current knowledge on the roles of the steroid hormone receptors [androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR), mineralocorticoid receptor (MR) and oestrogen receptor (ER)] in the lung, their effects on host cell proteins that facilitate SARS-CoV-2 uptake, and provides a snapshot of current clinical trials investigating the use of steroid receptor (SR) ligands to treat COVID-19.

COVID-19/metabolism , Lung/metabolism , Lung/virology , Receptors, Steroid/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , COVID-19/virology , Female , Hormone Antagonists/therapeutic use , Humans , Immunomodulation , Male , Receptors, Androgen/metabolism , Receptors, Estrogen/metabolism , Receptors, Glucocorticoid/metabolism , Receptors, Mineralocorticoid/metabolism , Receptors, Progesterone/metabolism , SARS-CoV-2 , Serine Endopeptidases/metabolism , Sex Factors
Cells ; 10(3)2021 03 05.
Article in English | MEDLINE | ID: covidwho-1129686


The superfamily of nuclear receptors (NRs), composed of ligand-activated transcription factors, is responsible for gene expression as a reaction to physiological and environmental changes. Transcriptional machinery may require phase separation to fulfil its role. Although NRs have a similar canonical structure, their C-terminal domains (F domains) are considered the least conserved and known regions. This article focuses on the peculiar molecular properties of the intrinsically disordered F domain of the ecdysteroid receptor from the Aedes aegypti mosquito (AaFEcR), the vector of the world's most devastating human diseases such as dengue and Zika. The His-Pro-rich segment of AaFEcR was recently shown to form the unique poly-proline helix II (PPII) in the presence of Cu2+. Here, using widefield microscopy of fluorescently labeled AaFEcR, Zn2+- and Cu2+-induced liquid-liquid phase separation (LLPS) was observed for the first time for the members of NRs. The perspectives of this finding on future research on the F domain are discussed, especially in relation to other NR members.

Ions/metabolism , Mosquito Vectors/pathogenicity , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Steroid/metabolism , Aedes , Animals , Humans
J Endocrinol ; 247(2): R45-R62, 2020 11.
Article in English | MEDLINE | ID: covidwho-793933


Coronavirus disease (COVID-19) is caused by a new strain of coronavirus, the severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2. At the time of writing, SARS-CoV-2 has infected over 5 million people worldwide. A key step in understanding the pathobiology of the SARS-CoV-2 was the identification of -converting enzyme 2 (ACE2) as the receptor for SARS-CoV-2 to gain entry into host cells. ACE2 is an established component of the 'protective arm' of the renin-angiotensin-aldosterone-system (RAAS) that opposes ACE/angiotensin II (ANG II) pressor and tissue remodelling actions. Identification of ACE2 as the entry point for SARS-CoV-2 into cells quickly focused attention on the use of ACE inhibitors (ACEi), angiotensin receptor blockers (ARB) and mineralocorticoid receptor antagonists (MRA) in patients with hypertension and cardiovascular disease given that these pharmacological agents upregulate ACE2 expression in target cells. ACE2 is cleaved from the cells by metalloproteases ADAM10 and ADAM17. Steroid hormone receptors regulate multiple components of the RAAS and may contribute to the observed variation in the incidence of severe COVID-19 between men and women, and in patients with pre-existing endocrine-related disease. Moreover, glucocorticoids play a critical role in the acute and chronic management of inflammatory disease, independent of any effect on RAAS activity. Dexamethasone, a synthetic glucocorticoid, has emerged as a life-saving treatment in severe COVID-19. This review will examine the endocrine mechanisms that control ACE2 and discusses the impact of therapies targeting the RAAS, glucocorticoid and other endocrine systems for their relevance to the impact of SARS-CoV-2 infection and the treatment and recovery from COVID-19-related critical illness.

Aldosterone/metabolism , Betacoronavirus/physiology , Coronavirus Infections/enzymology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/enzymology , Renin-Angiotensin System , Steroids/metabolism , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Animals , Betacoronavirus/genetics , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Humans , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Receptors, Steroid/genetics , Receptors, Steroid/metabolism , SARS-CoV-2