Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2.

Abstract:

:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, employs two key host proteins to gain entry and replicate within cells, angiotensin-converting enzyme 2 (ACE2) and the cell surface transmembrane protease serine 2 (TMPRSS2). TMPRSS2 was first characterized as an androgen-regulated gene in the prostate. Supporting a role for sex hormones, males relative to females are disproportionately affected by COVID-19 in terms of mortality and morbidity. Several studies, including one employing a large epidemiological cohort, suggested that blocking androgen signaling is protective against COVID-19. Here, we demonstrate that androgens regulate the expression of ACE2, TMPRSS2, and androgen receptor (AR) in subsets of lung epithelial cells. AR levels are markedly elevated in males relative to females greater than 70 y of age. In males greater than 70 y old, smoking was associated with elevated levels of AR and ACE2 in lung epithelial cells. Transcriptional repression of the AR enhanceosome with AR or bromodomain and extraterminal domain (BET) antagonists inhibited SARS-CoV-2 infection in vitro. Taken together, these studies support further investigation of transcriptional inhibition of critical host factors in the treatment or prevention of COVID-19.

authors

Qiao Y,Wang XM,Mannan R,Pitchiaya S,Zhang Y,Wotring JW,Xiao L,Robinson DR,Wu YM,Tien JC,Cao X,Simko SA,Apel IJ,Bawa P,Kregel S,Narayanan SP,Raskind G,Ellison SJ,Parolia A,Zelenka-Wang S,McMurry L,Su F,Wang R,

doi

10.1073/pnas.2021450118

subject

Has Abstract

pub_date

2020-12-11 00:00:00

eissn

0027-8424

issn

1091-6490

pii

2021450118

pub_type

杂志文章
  • Active auxin uptake by zucchini membrane vesicles: quantitation using ESR volume and delta pH determinations.

    abstract::Closed and pH-tight membrane vesicles prepared from hypocotyls of 5-day-old dark-grown seedlings of Cucurbita pepo accumulate the plant growth hormone indole-3-acetic acid along an imposed proton gradient (pH low outside, high inside). The use of electron paramagnetic spin probes permitted quantitation both of apparen...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.82.19.6541

    authors: Lomax TL,Mehlhorn RJ,Briggs WR

    更新日期:1985-10-01 00:00:00

  • Predicting coding function from nucleotide sequence or survival of "fitness" of tRNA.

    abstract::The sequence of a nucleotide region of f1 bacteriophage was determined on a bonded ultrathin acrylamide gel with a discontinuous buffer system by using the dideoxy-DNA sequencing method. This sequence and one other were analyzed for maximal base pairing with tRNAs. The results allow a prediction of the direction and p...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.77.6.3539

    authors: Pieczenik G

    更新日期:1980-06-01 00:00:00

  • Interference with ERK(Thr188) phosphorylation impairs pathological but not physiological cardiac hypertrophy.

    abstract::Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are central mediators of cardiac hypertrophy and are discussed as potential therapeutic targets. However, direct inhibition of ERK1/2 leads to exacerbated cardiomyocyte death and impaired heart function. We have previously identified ERK(Thr188) autophosphorylati...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1221999110

    authors: Ruppert C,Deiss K,Herrmann S,Vidal M,Oezkur M,Gorski A,Weidemann F,Lohse MJ,Lorenz K

    更新日期:2013-04-30 00:00:00

  • Interactions of a Rel protein with its inhibitor.

    abstract::Cactus, a Drosophila homologue of I kappa B, binds to and inhibits Dorsal, a homologue of the p50 and p65 components of NF-kappa B. We describe experiments in yeast with various Dorsal and Cactus derivatives showing that Cactus blocks the DNA binding and nuclear localization functions of Dorsal. In contrast, Dorsal's ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.92.22.10242

    authors: Lehming N,McGuire S,Brickman JM,Ptashne M

    更新日期:1995-10-24 00:00:00

  • Cellular mechanisms for the formation of a soluble form derivative of T-cell receptor alpha chain by suppressor T cells.

    abstract::Upon stimulation with anti-CD3, suppressor T-cell (Ts) hybridomas and homologous transfectants of T-cell receptor a (TCRalpha) cDNA in the T-cell hybridoma formed a 55-kDa TCRalpha chain derivative that bound both the monoclonal anti-TCRalpha chain and polyclonal antibodies against glycosylation inhibiting factor (GIF...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.93.14.7207

    authors: Ishii Y,Nakano T,Ishizaka K

    更新日期:1996-07-09 00:00:00

  • Force production by depolymerizing microtubules: a theoretical study.

    abstract::Chromosome movement during mitosis is powered in part by energy released through the depolymerization of kinetochore microtubules (MTs). Strong but indirect evidence suggests the existence of a specialized coupling between kinetochores and MT plus ends that enables this transduction of chemical energy into mechanical ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0501142102

    authors: Molodtsov MI,Grishchuk EL,Efremov AK,McIntosh JR,Ataullakhanov FI

    更新日期:2005-03-22 00:00:00

  • One SUMO is sufficient to silence the dimeric potassium channel K2P1.

    abstract::Small ubiquitin modifier 1 (SUMO1) is shown to regulate K2P1 background channels in the plasma membrane (PM) of live mammalian cells. Confocal microscopy reveals native SUMO1, SAE1, and Ubc9 (the enzymes that activate and conjugate SUMO1) at PM where SUMO1 and expressed human K2P1 are demonstrated to colocalize. Silen...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1004712107

    authors: Plant LD,Dementieva IS,Kollewe A,Olikara S,Marks JD,Goldstein SA

    更新日期:2010-06-08 00:00:00

  • The influence of short-range interactions on protein onformation. II. A model for predicting the alpha-helical regions of proteins.

    abstract::On the basis of earlier energy computations, the various single peptide units in proteins were designated as helix-making or helix-breaking.(1) With the use of these designations, empirical rules for distinguishing between alpha-helical and non-alpha-helical regions of proteins have been formulated. These rules includ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.62.1.14

    authors: Kotelchuck D,Scheraga HA

    更新日期:1969-01-01 00:00:00

  • VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKC{delta}-driven migration.

    abstract::A common genetic mutation found in clear cell renal cell carcinoma (CC-RCC) is the loss of the von Hippel-Lindau (VHL) gene, which results in stabilization of hypoxia-inducible factors (HIFs), and contributes to cancer progression and metastasis. CUB-domain-containing protein 1 (CDCP1) was shown to promote metastasis ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1011777108

    authors: Razorenova OV,Finger EC,Colavitti R,Chernikova SB,Boiko AD,Chan CK,Krieg A,Bedogni B,LaGory E,Weissman IL,Broome-Powell M,Giaccia AJ

    更新日期:2011-02-01 00:00:00

  • A maize sesquiterpene cyclase gene induced by insect herbivory and volicitin: characterization of wild-type and mutant alleles.

    abstract::Plants can defend themselves from herbivorous insects by emitting volatile chemical signals that attract natural enemies of the herbivore. For example, maize seedlings attacked by beet armyworm larvae (Spodoptera exigua) produce a mixture of terpenoid and indole volatiles that serve to attract parasitic wasps. A key s...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.240284097

    authors: Shen B,Zheng Z,Dooner HK

    更新日期:2000-12-19 00:00:00

  • Identification of slow correlated motions in proteins using residual dipolar and hydrogen-bond scalar couplings.

    abstract::Despite their importance for biological activity, slower molecular motions beyond the nanosecond range remain poorly understood. We have assembled an unprecedented set of experimental NMR data, comprising up to 27 residual dipolar couplings per amino acid, to define the nature and amplitude of backbone motion in prote...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0505129102

    authors: Bouvignies G,Bernadó P,Meier S,Cho K,Grzesiek S,Brüschweiler R,Blackledge M

    更新日期:2005-09-27 00:00:00

  • FGFR1-mediated protocadherin-15 loading mediates cargo specificity during intraflagellar transport in inner ear hair-cell kinocilia.

    abstract::The mechanosensory hair cells of the inner ear are required for hearing and balance and have a distinctive apical structure, the hair bundle, that converts mechanical stimuli into electrical signals. This structure comprises a single cilium, the kinocilium, lying adjacent to an ensemble of actin-based projections know...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1719861115

    authors: Honda A,Kita T,Seshadri SV,Misaki K,Ahmed Z,Ladbury JE,Richardson GP,Yonemura S,Ladher RK

    更新日期:2018-08-14 00:00:00

  • Identification of the 5' end of Rous sarcoma virus RNA.

    abstract::The 5'-terminal triphosphate of the 35S RNA isolated from Rous sarcoma virus is blocked by 7-methylguanosine in 5' linkage with the penultimate nucleoside which is methylated in the 2'-O-ribose position, a type of endgroup found in all animal mRNAs investigated during the past year. The specific nuclease-resistant ter...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.72.9.3347

    authors: Keith J,Fraenkel-Conrat H

    更新日期:1975-09-01 00:00:00

  • Wind directions aloft and effects of seeding on precipitation in the whitetop experiment.

    abstract::The subdivision of all the experimental days of the Whitetop project into two approximately equal groups, group W with predominantly westerly winds aloft and group E with frequent easterly winds, shows a remarkable difference in the apparent effect of seeding. On W days there was no detectable effect of seeding on rai...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.64.3.810

    authors: Lovasich JL,Neyman J,Scott EL,Smith JA

    更新日期:1969-11-01 00:00:00

  • Primary structure, chromosomal localization, and functional expression of a voltage-gated sodium channel from human brain.

    abstract::A cDNA library derived from human cerebral cortex was screened for the presence of sodium channel alpha subunit-specific clones. Ligation of three overlapping clones generated a full-length cDNA clone, HBA, that provided the complete nucleotide sequence coding for a protein of 2005 amino acids. The predicted structure...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.89.17.8220

    authors: Ahmed CM,Ware DH,Lee SC,Patten CD,Ferrer-Montiel AV,Schinder AF,McPherson JD,Wagner-McPherson CB,Wasmuth JJ,Evans GA

    更新日期:1992-09-01 00:00:00

  • CD22 ligand-binding and signaling domains reciprocally regulate B-cell Ca2+ signaling.

    abstract::A high proportion of human B cells carry B-cell receptors (BCRs) that are autoreactive. Inhibitory receptors such as CD22 can downmodulate autoreactive BCR responses. With its extracellular domain, CD22 binds to sialic acids in α2,6 linkages in cis, on the surface of the same B cell or in trans, on other cells. Sialic...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1304888110

    authors: Müller J,Obermeier I,Wöhner M,Brandl C,Mrotzek S,Angermüller S,Maity PC,Reth M,Nitschke L

    更新日期:2013-07-23 00:00:00

  • Release of 1-O-alkylglyceryl 3-phosphorylcholine, O-deacetyl platelet-activating factor, from leukocytes: chemical ionization mass spectrometry of phospholipids.

    abstract::Evidence is presented for the simultaneous release of platelet-activating factor (PAF-acether) and of its deacetylated derivative (lyso-PAF-acether) from hog leukocytes. On the basis of spectroscopy and chemical reactions, the structure of O-deacetyl-PAF is shown to be 1-O-alkylglyceryl 3-phosphorylcholine, an alkyl e...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.77.12.7019

    authors: Polonsky J,Tencé M,Varenne P,Das BC,Lunel J,Benveniste J

    更新日期:1980-12-01 00:00:00

  • Latent infection membrane protein transmembrane FWLY is critical for intermolecular interaction, raft localization, and signaling.

    abstract::Relatively little is known about the biochemical mechanisms through which the Epstein-Barr virus latent infection integral membrane protein 1 (LMP1) transmembrane domains cause constitutive LMP1 aggregation and continuous cytoplasmic C terminus-mediated signal transduction. We now evaluate the role of the three consec...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2237224100

    authors: Yasui T,Luftig M,Soni V,Kieff E

    更新日期:2004-01-06 00:00:00

  • Warfare and reproductive success in a tribal population.

    abstract::Intergroup conflict is a persistent feature of many human societies yet little is known about why individuals participate when doing so imposes a mortality risk. To evaluate whether participation in warfare is associated with reproductive benefits, we present data on participation in small-scale livestock raids among ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1412287112

    authors: Glowacki L,Wrangham R

    更新日期:2015-01-13 00:00:00

  • Three-body interactions improve the prediction of rate and mechanism in protein folding models.

    abstract::Here we study the effects of many-body interactions on rate and mechanism in protein folding by using the results of molecular dynamics simulations on numerous coarse-grained Calpha-model single-domain proteins. After adding three-body interactions explicitly as a perturbation to a Gō-like Hamiltonian with native pair...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0403486101

    authors: Ejtehadi MR,Avall SP,Plotkin SS

    更新日期:2004-10-19 00:00:00

  • Identification of a gene that positively regulates expression of listeriolysin, the major virulence factor of listeria monocytogenes.

    abstract::We have isolated, by molecular cloning and genetic complementation of a listeriolysin-negative mutant, a gene required for the expression of this virulence factor in Listeria monocytogenes. The mutant strain SLCC53, which was nonhemolytic and avirulent, harbored a deletion of 450 base pairs located approximately 1500 ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.87.21.8336

    authors: Leimeister-Wächter M,Haffner C,Domann E,Goebel W,Chakraborty T

    更新日期:1990-11-01 00:00:00

  • Effects of the peer metagenomic environment on smoking behavior.

    abstract::Recent scholarship suggests that the genomes of those around us affect our own phenotypes. Much of the empirical evidence for such "metagenomic" effects comes from animal studies, where the socio-genetic environment can be easily manipulated. Among humans, it is more difficult to identify such effects given the nonran...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1806901116

    authors: Sotoudeh R,Harris KM,Conley D

    更新日期:2019-08-13 00:00:00

  • Wnt signaling and a Smad pathway blockade direct the differentiation of human pluripotent stem cells to multipotent neural crest cells.

    abstract::Neural crest stem cells can be isolated from differentiated cultures of human pluripotent stem cells, but the process is inefficient and requires cell sorting to obtain a highly enriched population. No specific method for directed differentiation of human pluripotent cells toward neural crest stem cells has yet been r...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1113746108

    authors: Menendez L,Yatskievych TA,Antin PB,Dalton S

    更新日期:2011-11-29 00:00:00

  • Analysis of chromosomal instability in human colorectal adenomas with two mutational hits at APC.

    abstract::In vitro data show that the adenomatous polyposis coli (APC) protein associates with the mitotic spindle and that mouse embryonic stem cells with biallelic Apc mutations are karyotypically unstable. These findings led to suggestions that APC acts in chromosomal segregation and that APC inactivation leads to chromosoma...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.012679099

    authors: Sieber OM,Heinimann K,Gorman P,Lamlum H,Crabtree M,Simpson CA,Davies D,Neale K,Hodgson SV,Roylance RR,Phillips RK,Bodmer WF,Tomlinson IP

    更新日期:2002-12-24 00:00:00

  • Primarily chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities.

    abstract::HLA class II gene polymorphism was investigated in 100 patients with clinically definite multiple sclerosis (MS) by restriction fragment length polymorphism analysis of Taq I-digested DNA using DRB, DQA, and DQB cDNA probes. Twenty-six patients had primarily chronic progressive MS and 74 had relapsing/remitting MS. Th...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.18.7113

    authors: Olerup O,Hillert J,Fredrikson S,Olsson T,Kam-Hansen S,Möller E,Carlsson B,Wallin J

    更新日期:1989-09-01 00:00:00

  • Selective visual representation of letters and words in the left ventral occipito-temporal cortex with intracerebral recordings.

    abstract::We report a comprehensive cartography of selective responses to visual letters and words in the human ventral occipito-temporal cortex (VOTC) with direct neural recordings, clarifying key aspects of the neural basis of reading. Intracerebral recordings were performed in a large group of patients (n = 37) presented wit...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1718987115

    authors: Lochy A,Jacques C,Maillard L,Colnat-Coulbois S,Rossion B,Jonas J

    更新日期:2018-08-07 00:00:00

  • In vitro assembly of a functional nucleocapsid from the negative-stranded genome RNA of a defective interfering particle of vesicular stomatitis virus.

    abstract::The template for transcription and replication of negative-stranded RNA viruses is a ribonucleoprotein structure, the nucleocapsid. We have developed a system that supports assembly of the negative-stranded RNA genome of a defective interfering (DI) particle of vesicular stomatitis virus (VSV) into a nucleocapsid in v...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.85.20.7511

    authors: Mirakhur B,Peluso RW

    更新日期:1988-10-01 00:00:00

  • Absence of serum growth hormone binding protein in patients with growth hormone receptor deficiency (Laron dwarfism).

    abstract::It has recently been recognized that human serum contains a protein that specifically binds human growth hormone (hGH). This protein has the same restricted specificity for hGH as the membrane-bound GH receptor. To determine whether the GH-binding protein is a derivative of, or otherwise related to, the GH receptor, w...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.84.13.4636

    authors: Daughaday WH,Trivedi B

    更新日期:1987-07-01 00:00:00

  • Cultured aortic endothelial cells from pigs with von Willebrand disease: in vitro model for studying the molecular defect(s) of the disease.

    abstract::Aortic endothelial cells from normal pigs and pigs with von Willebrand disease have been established in long-term cultures. Both cultures appeared similar in terms of general growth characteristics, morphologic features and ultrastructure. Immunofluorescent staining of these cultures with chicken (or rabbit) antiporci...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.74.12.5702

    authors: Booyse FM,Quarfoot AJ,Bell S,Fass DN,Lewis JC,Mann KG,Bowie EJ

    更新日期:1977-12-01 00:00:00

  • Spatiotemporal reaction kinetics of an ultrafast photoreaction pathway visualized by time-resolved liquid x-ray diffraction.

    abstract::We have studied the reaction dynamics for HgI(2) in methanol by using time-resolved x-ray diffraction (TRXD). Although numerous time-resolved spectroscopic studies have provided ample information about the early dynamics of HgI(2), a comprehensive reaction mechanism in the solution phase spanning from picoseconds up t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0601958103

    authors: Kim TK,Lorenc M,Lee JH,Lo Russo M,Kim J,Cammarata M,Kong Q,Noel S,Plech A,Wulff M,Ihee H

    更新日期:2006-06-20 00:00:00