Potassium molybdate blocks APN-dependent coronavirus entry by degrading receptor via PIK3C3-mediated autophagy
Yunhang ZhangNa ZhangYue ZhangYang LiNing YangYifei CaiChen TanJing ZhaoWenjie LiYuanyuan LiuRui XueJunfei WuYuguang FuGuangliang Liu
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Abstract:
Swine enteric coronaviruses pose a significant challenge to the global pig industry, inflicting severe diarrhea and high mortality rates among piglets, and resulting in substantial economic losses. In our clinical practice, we observed that the addition of potassium molybdate (PM) to the feed could dramatically reduce diarrhea and diarrhea-related mortality in piglets. However, the underlying mechanisms remain elusive and merit further investigation. In this study, we revealed that PM effectively inhibited the infection of both aminopeptidase N (APN)-dependent coronaviruses, transmissible gastroenteritis virus (TGEV), and porcine respiratory coronavirus (PRCV), both in vitro and ex vivo. Specifically, PM was found to block TGEV and PRCV penetration by degrading the cell receptor APN through the upregulation of phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) expression. In addition, knockdown and knockout of PIK3C3 resulted in the attenuation of PM-induced autophagy, thereby rescuing APN expression and viral infection. Correspondingly, replenishment of PIK3C3 in PIK3C3-null ST cells restored PM-mediated APN degradation and successfully blocked viral entry. Furthermore, our findings demonstrated that PM promoted the assembly of the PIK3C3-BECN1-ATG14 complex, leading to induced autophagic degradation by upregulating PIK3C3 Ser249 phosphorylation. In vivo experiments further confirmed that PM-induced PIK3C3-mediated autophagic degradation of APN, thereby limiting the pathogenicity of TGEV. In summary, our study for the first time identified the mechanism by which PM blocked TGEV and PRCV internalization by degrading the cell receptor APN via PIK3C3-mediated autophagy. This study provides valuable insights and potential strategies for preventing APN-restricted coronavirus infection.IMPORTANCEAminopeptidase N (APN) is one of the most important host receptors of coronavirus. Modulating APN expression can represent a novel approach for controlling APN-dependent coronaviruses and their variants infection. Here we found that a chemical compound potassium molybdate (PM) negatively regulates APN expression by inducing phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3)-mediated autophagy against APN-dependent coronavirus internalization, including transmissible gastroenteritis virus (TGEV) and porcine respiratory coronavirus (PRCV). Furthermore, PM can promote PIK3C3-BECN1-ATG14 complex assembly to induce autophagic degradation of APN by upregulating PIK3C3 Ser249 phosphorylation. Lastly, results from pig experiments also confirmed that PM can trigger PIK3C3-mediated autophagic degradation of APN to restrict TGEV pathogenicity in vivo without toxicity. Our findings underscore the promising potential of PM as an effective agent against APN-dependent coronavirus and potentially emerging viral disease entry.Keywords:
Coronavirus
2019-20 coronavirus outbreak
Sodium molybdate
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTElectrical conductance and density in the fused molybdate systems, lithium molybdate-sodium molybdate and lithium molybdate-potassium molybdateKelso Bronson. Morris and L. Pearl. BrownCite this: J. Chem. Eng. Data 1971, 16, 2, 210–211Publication Date (Print):April 1, 1971Publication History Published online1 May 2002Published inissue 1 April 1971https://pubs.acs.org/doi/10.1021/je60049a025https://doi.org/10.1021/je60049a025research-articleACS PublicationsRequest reuse permissionsArticle Views46Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
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The present study describes the effects of sodium molybdate on several physicochemical properties of the androgen receptor from the Dunning R3327 prostatic tumor. Molybdate was found to stabilize the steroid-binding activity of the receptor. Maximum binding activity was found with concentrations of 10 mm molybdate or greater. Density gradient and gel filtration analyses of the receptor revealed an 8.5–9.0S, 68Å form (mol wt, ∼265,000–275,000) in either the presence or absence of molybdate (20 mm) when determined under low ionic conditions. Under high ionic conditions (400 mm KC1), the receptor was maintained in a similar form (8.5–9.0S; 72–73Å mol wt, ∼275,000–295,000) in the presence of molybdate; however, it disaggregated to a smaller 4.4S, 61 Å form (mol wt, ∼120,000) in the absence of molybdate. Affinity labeling of the receptor with 17β-[(bromoacetyl)oxy]-[l,2,4,5)6,7,16)17-3H8]5α-androstan- 3-one showed a mol wt of 118,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography. Molybdate inhibited the salt-induced transformation of the receptor to a DNA-binding state, but did not inhibit the DNA binding of the receptor transformed previously in the absence of molybdate. These studies suggest that sodium molybdate stabilizes the steroid-binding activity of the androgen receptor in an aggregated nontransformed state. (Endocrinology114: 1776, 1984)
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Abstract Inhibition of 3′:5′-cyclic-AMP-5′-nucleotidohydrolase (EC 3.1.4.17) type II (cAMP-phosphodiesterase) by sodium molybdate was studied: While determination of inorganic phosphate and 5′-ribonucleotide phosphohydrolase (5′-nucleotidase) (EC 3.1.3.5) activity was not disturbed by sodium molybdate in concentrations up to 10 mM , cAMP-phosphodiesterase was inhibited by millimolar concentrations of molybdate. The half maximal effect was observed at about 2 mM sodium molybdate (0.75 mM cAMP in the assay).
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Abstract The ability of sodium molybdate to inhibit corrosion of mild steel is demonstrated using laboratory and field test data. Initial evidence is also presented indicating that molybdate inhibits the corrosion of copper and aluminium. Environmental aspects including fish toxicity data are discussed as is the likely mechanism of molybdate inhibition.
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A range of levels of sodium molybdate was applied to existing clover pastures at Boyup Brook and at Bakers Hill in south-western Australia. In the three subsequent years, further levels of molybdate were applied to some of the sites to assess the residual value of the initial application. The effect of the molybdate application on the molybdenum concentration in clover tops was measured. Plots of molybdenum concentration in tops versus molybdate applied curved upwards at first as each additional increment provided an increased response in concentration. However, at high concentrations of molybdate in clover tops the plots curved to the right at three out of four sites as each additional increment produced a decreased response. That is, overall, the curves were sigmoid. Increases in molybdate concentration were greatest on soils with least ability to retain molybdate as measured in the laboratory. Molybdate applied one year previously was about half as effective as currently applied molybdate. After two and three years it was about 20% as effective. A single application of rnolybdate remains effective for a long period on a soil of low ability to retain molybdate because the initial application is super-abundant - rather than because of large differences between soils in the rate of decline of effectiveness.
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The effects of sodium molybdate on the transformation of mouse uterine cytoplasmic estradiol . receptor complex has been studied. If molybdate is added to cytosol containing the nontransformed estradiol . receptor complex, it blocks the receptor transformation which otherwise occurs during incubation at 28 degrees C. The inhibition by molybdate is apparent both in sucrose gradient centrifugation analyses of estradiol . receptor complexes and [3H]estradiol dissociation kinetic studies. A molybdate-sensitive change of the nontransformed estradiol . receptor complex can also be inferred from behavior of the estradiol . receptor complex on low ionic strength sucrose gradients.
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