{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T11:25:42Z","timestamp":1767180342972,"version":"build-2238731810"},"update-to":[{"DOI":"10.1371\/journal.pgen.1011896","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000}}],"reference-count":103,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004792","name":"Minist\u00c3\u00a8re de l'Enseignement Sup\u00c3\u00a9rieur et de la Recherche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004792","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-17-EURE-0013"],"award-info":[{"award-number":["ANR-17-EURE-0013"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-23-CE13-0012-01"],"award-info":[{"award-number":["ANR-23-CE13-0012-01"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    The yeast\n                    <jats:italic>\n                      <jats:italic>Saccharomyces cerevisiae<\/jats:italic>\n                    <\/jats:italic>\n                    thrives in sugar-rich environments by rapidly consuming glucose and favoring alcoholic fermentation. This strategy is tightly regulated by the glucose repression pathway, which prevents the expression of genes required for the utilization of alternative carbon source. Central to this regulatory network is the yeast ortholog of the heterotrimeric 5\u2032AMP-activated protein kinase (AMPK), which adjusts gene expression in response to glucose availability. The activity of the yeast AMPK complex is primarily regulated by the phosphorylation state of its catalytic subunit Snf1, a process orchestrated by a balance between upstream kinases and phosphatases. Among the latter, the Protein Phosphatase 1 (PP1) complex Reg1\/Glc7 plays a critical role in inhibiting Snf1 activity under glucose-rich conditions. Despite its importance, the precise mechanism by which glucose availability leads to Snf1 inhibition remains incompletely understood. Evidence suggests that hexokinase 2 (Hxk2) participates in this pathway, potentially coupling the early steps of glucose metabolism to Snf1 signaling. Notably, the toxic glucose analog 2-deoxyglucose (2DG)- which is phosphorylated by Hxk2 but not further metabolized- mimics glucose in its ability to repress Snf1, implicating glucose or 2DG phosphorylation as a key regulatory signal. Additionally, yeast AMPK activity correlates with 2DG resistance through mechanisms that are incompletely described. In this study, we performed a large-scale 2DG-resistance genetic screen to explore both the molecular basis of 2DG resistance and AMPK regulation in yeast. The identified mutations confer resistance either by reducing 2DG phosphorylation (e.g., mutations in\n                    <jats:italic>HXK2<\/jats:italic>\n                    ) or by enhancing constitutive Snf1 activity, via gain-of-function alleles in AMPK subunits or loss-of-function mutations in\n                    <jats:italic>REG1<\/jats:italic>\n                    and\n                    <jats:italic>GLC7<\/jats:italic>\n                    . We also describe a novel series of\n                    <jats:italic>REG1<\/jats:italic>\n                    missense mutations, including\n                    <jats:italic>\n                      <jats:italic>reg1-W165G<\/jats:italic>\n                    <\/jats:italic>\n                    , that maintain basal, glucose-regulated Snf1 activity but fail to mediate 2DG-induced Snf1 inhibition. These findings position Reg1 as a central mediator in glucose sensing, possibly by sensing 2DG-derived -and by extension, glucose-derived- metabolites.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1011896","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:07:17Z","timestamp":1760033237000},"page":"e1011896","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["A genetic screen reveals a key role for Reg1 in 2-deoxyglucose sensing and yeast AMPK inhibition"],"prefix":"10.1371","volume":"21","author":[{"given":"Alberto","family":"Ballin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5947-7415","authenticated-orcid":true,"given":"V\u00e9ronique","family":"Alban\u00e8se","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8561-3193","authenticated-orcid":true,"given":"Samia","family":"Miled","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V\u00e9ronique","family":"Legros","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guillaume","family":"Chevreux","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agathe","family":"Verraes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3558-9356","authenticated-orcid":true,"given":"Anne","family":"Friedrich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2536-8595","authenticated-orcid":true,"given":"S\u00e9bastien","family":"L\u00e9on","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"issue":"2","key":"pgen.1011896.ref001","doi-asserted-by":"crossref","first-page":"230","DOI":"10.3390\/genes13020230","article-title":"The 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Yang","year":"1994","journal-title":"EMBO J"},{"issue":"2","key":"pgen.1011896.ref014","first-page":"83","article-title":"Isolation and characterization of dominant mutations resistant to carbon catabolite repression of galactokinase synthesis in Saccharomyces cerevisiae","volume":"1","author":"K Matsumoto","year":"1981","journal-title":"Mol Cell Biol"},{"issue":"3","key":"pgen.1011896.ref015","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1093\/genetics\/135.3.655","article-title":"Genetic and molecular characterization of GAL83: its interaction and similarities with other genes involved in glucose repression in Saccharomyces cerevisiae","volume":"135","author":"JR Erickson","year":"1993","journal-title":"Genetics"},{"issue":"3","key":"pgen.1011896.ref016","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1128\/MCB.16.3.753","article-title":"Functional domains in the Mig1 repressor","volume":"16","author":"J Ostling","year":"1996","journal-title":"Mol Cell 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Vallier","year":"1994","journal-title":"Genetics"},{"issue":"6","key":"pgen.1011896.ref023","first-page":"3834","article-title":"Multiple mechanisms provide rapid and stringent glucose repression of GAL gene expression in Saccharomyces cerevisiae","volume":"14","author":"M Johnston","year":"1994","journal-title":"Mol Cell Biol"},{"issue":"3","key":"pgen.1011896.ref024","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1128\/jb.121.3.747-752.1975","article-title":"Isolation of a catabolite repression mutant of yeast as a revertant of a strain that is maltose negative in the respiratory-deficient state","volume":"121","author":"DH Schamhart","year":"1975","journal-title":"J Bacteriol"},{"issue":"39","key":"pgen.1011896.ref025","first-page":"36460","article-title":"Regulation of Snf1 kinase. Activation requires phosphorylation of threonine 210 by an upstream kinase as well as a distinct step mediated by the Snf4 subunit","volume":"276","author":"RR McCartney","year":"2001","journal-title":"J Biol Chem"},{"issue":"24","key":"pgen.1011896.ref026","doi-asserted-by":"crossref","first-page":"3105","DOI":"10.1101\/gad.10.24.3105","article-title":"Glucose regulates protein interactions within the yeast SNF1 protein kinase complex","volume":"10","author":"R Jiang","year":"1996","journal-title":"Genes Dev"},{"issue":"11","key":"pgen.1011896.ref027","doi-asserted-by":"crossref","first-page":"6245","DOI":"10.1073\/pnas.95.11.6245","article-title":"Glucose-regulated interaction of a regulatory subunit of protein phosphatase 1 with the Snf1 protein kinase in Saccharomyces cerevisiae","volume":"95","author":"K Ludin","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"15","key":"pgen.1011896.ref028","doi-asserted-by":"crossref","first-page":"8839","DOI":"10.1073\/pnas.1533136100","article-title":"Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases","volume":"100","author":"S-P Hong","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"15","key":"pgen.1011896.ref029","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1016\/S0960-9822(03)00459-7","article-title":"Elm1p is one of three upstream kinases for the Saccharomyces cerevisiae SNF1 complex","volume":"13","author":"CM Sutherland","year":"2003","journal-title":"Curr Biol"},{"issue":"11","key":"pgen.1011896.ref030","doi-asserted-by":"crossref","first-page":"3909","DOI":"10.1128\/MCB.23.11.3909-3917.2003","article-title":"Yeast Pak1 kinase associates with and activates Snf1","volume":"23","author":"N Nath","year":"2003","journal-title":"Mol Cell Biol"},{"issue":"1","key":"pgen.1011896.ref031","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1074\/jbc.M707957200","article-title":"Access denied: Snf1 activation loop phosphorylation is controlled by availability of the phosphorylated threonine 210 to the PP1 phosphatase","volume":"283","author":"EM Rubenstein","year":"2008","journal-title":"J Biol Chem"},{"issue":"3","key":"pgen.1011896.ref032","first-page":"522","article-title":"Repression by glucose of alcohol dehydrogenase, malate dehydrogenase, isocitrate lyase and malate synthase in yeast","volume":"118","author":"I Witt","year":"1966","journal-title":"Biochim Biophys Acta"},{"issue":"3","key":"pgen.1011896.ref033","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/BF00333160","article-title":"Genetic control of invertase formation in Saccharomyces cerevisiae. II. Isolation and characterization of mutants conferring invertase hyperproduction in strain EK-6B carrying the SUC3 gene","volume":"164","author":"RA Hackel","year":"1978","journal-title":"Mol Gen Genet"},{"key":"pgen.1011896.ref034","doi-asserted-by":"crossref","first-page":"114213","DOI":"10.1016\/j.bcp.2020.114213","article-title":"Cellular toxicity of the metabolic inhibitor 2-deoxyglucose and associated resistance mechanisms","volume":"182","author":"C Laussel","year":"2020","journal-title":"Biochem Pharmacol"},{"issue":"2","key":"pgen.1011896.ref035","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1093\/genetics\/115.2.247","article-title":"Mutations causing constitutive invertase synthesis in yeast: genetic interactions with snf mutations","volume":"115","author":"L Neigeborn","year":"1987","journal-title":"Genetics"},{"issue":"4","key":"pgen.1011896.ref036","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1128\/MCB.20.4.1321-1328.2000","article-title":"Regulatory interactions between the Reg1-Glc7 protein phosphatase and the Snf1 protein kinase","volume":"20","author":"P Sanz","year":"2000","journal-title":"Mol Cell Biol"},{"issue":"23","key":"pgen.1011896.ref037","doi-asserted-by":"crossref","first-page":"5939","DOI":"10.1002\/j.1460-2075.1995.tb00282.x","article-title":"REG1 binds to protein phosphatase type 1 and regulates glucose repression in Saccharomyces cerevisiae","volume":"14","author":"J Tu","year":"1995","journal-title":"EMBO J"},{"issue":"10","key":"pgen.1011896.ref038","first-page":"6789","article-title":"The GLC7 type 1 protein phosphatase is required for glucose repression in Saccharomyces cerevisiae","volume":"14","author":"J Tu","year":"1994","journal-title":"Mol Cell 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Winde","year":"1996","journal-title":"Eur J Biochem"},{"issue":"2","key":"pgen.1011896.ref045","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1534\/genetics.114.169060","article-title":"Genetic analysis of resistance and sensitivity to 2-deoxyglucose in Saccharomyces cerevisiae","volume":"198","author":"RR McCartney","year":"2014","journal-title":"Genetics"},{"issue":"7","key":"pgen.1011896.ref046","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1008484","article-title":"Spontaneous mutations that confer resistance to 2-deoxyglucose act through Hxk2 and Snf1 pathways to regulate gene expression and HXT endocytosis","volume":"16","author":"SR Soncini","year":"2020","journal-title":"PLoS Genet"},{"issue":"11","key":"pgen.1011896.ref047","doi-asserted-by":"crossref","first-page":"6273","DOI":"10.1128\/MCB.18.11.6273","article-title":"Snf1 protein kinase regulates phosphorylation of the Mig1 repressor in Saccharomyces cerevisiae","volume":"18","author":"MA Treitel","year":"1998","journal-title":"Mol Cell Biol"},{"issue":"7","key":"pgen.1011896.ref048","doi-asserted-by":"crossref","first-page":"4485","DOI":"10.1074\/jbc.M606854200","article-title":"Hxk2 regulates the phosphorylation state of Mig1 and therefore its nucleocytoplasmic distribution","volume":"282","author":"D Ahuatzi","year":"2007","journal-title":"J Biol Chem"},{"issue":"5","key":"pgen.1011896.ref049","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1010745","article-title":"Changing course: Glucose starvation drives nuclear accumulation of Hexokinase 2 in S. cerevisiae","volume":"19","author":"MA Lesko","year":"2023","journal-title":"PLoS Genet"},{"issue":"8","key":"pgen.1011896.ref050","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1010169","article-title":"2-deoxyglucose transiently inhibits yeast AMPK signaling and triggers glucose transporter endocytosis, potentiating the drug toxicity","volume":"18","author":"C Laussel","year":"2022","journal-title":"PLoS Genet"},{"issue":"2","key":"pgen.1011896.ref051","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/BF00315774","article-title":"The expression of a specific 2-deoxyglucose-6P phosphatase prevents catabolite repression mediated by 2-deoxyglucose in yeast","volume":"28","author":"F Randez-Gil","year":"1995","journal-title":"Curr Genet"},{"issue":"46","key":"pgen.1011896.ref052","doi-asserted-by":"crossref","first-page":"17807","DOI":"10.1073\/pnas.0803090105","article-title":"A catabolic block does not sufficiently explain how 2-deoxy-D-glucose inhibits cell growth","volume":"105","author":"M Ralser","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"597","key":"pgen.1011896.ref053","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.aaw8000","article-title":"The induction of HAD-like phosphatases by multiple signaling pathways confers resistance to the metabolic inhibitor 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Drug resistance in diploid yeast is acquired through dominant alleles, haploinsufficiency, gene duplication and aneuploidy. 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Becuwe","year":"2014","journal-title":"Elife"},{"issue":"25","key":"pgen.1011896.ref081","doi-asserted-by":"crossref","first-page":"7410","DOI":"10.1021\/bi002796k","article-title":"Mutations in yeast protein phosphatase type 1 that affect targeting subunit binding","volume":"40","author":"X Wu","year":"2001","journal-title":"Biochemistry"},{"issue":"8","key":"pgen.1011896.ref082","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1093\/emboj\/16.8.1876","article-title":"Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1","volume":"16","author":"MP Egloff","year":"1997","journal-title":"EMBO J"},{"issue":"2","key":"pgen.1011896.ref083","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1111\/j.1742-4658.2012.08547.x","article-title":"The PP1 binding code: a molecular-lego strategy that governs specificity","volume":"280","author":"E Heroes","year":"2013","journal-title":"FEBS 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Microbiol"},{"key":"pgen.1011896.ref087","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/S0014-5793(03)00498-8","article-title":"Saccharomyces cerevisiae 14-3-3 proteins Bmh1 and Bmh2 participate in the process of catabolite inactivation of maltose permease","volume":"544","author":"I Mayordomo","year":"2003","journal-title":"FEBS Lett"},{"issue":"37","key":"pgen.1011896.ref088","doi-asserted-by":"crossref","first-page":"39165","DOI":"10.1074\/jbc.M400433200","article-title":"The Reg1-interacting proteins, Bmh1, Bmh2, Ssb1, and Ssb2, have roles in maintaining glucose repression in Saccharomyces cerevisiae","volume":"279","author":"KM Dombek","year":"2004","journal-title":"J Biol Chem"},{"issue":"3","key":"pgen.1011896.ref089","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1021\/acssensors.9b02475","article-title":"An Improved ATP FRET Sensor For Yeast Shows Heterogeneity During Nutrient Transitions","volume":"5","author":"D Botman","year":"2020","journal-title":"ACS Sens"},{"issue":"8","key":"pgen.1011896.ref090","doi-asserted-by":"crossref","DOI":"10.1083\/jcb.202012104","article-title":"ESCRT, not intralumenal fragments, sorts ubiquitinated vacuole membrane proteins for degradation","volume":"220","author":"X Yang","year":"2021","journal-title":"J Cell Biol"},{"issue":"25","key":"pgen.1011896.ref091","doi-asserted-by":"crossref","first-page":"4618","DOI":"10.1091\/mbc.E15-06-0344","article-title":"Target of rapamycin signaling mediates vacuolar fission caused by endoplasmic reticulum stress in Saccharomyces cerevisiae","volume":"26","author":"B Stauffer","year":"2015","journal-title":"Mol Biol Cell"},{"issue":"13","key":"pgen.1011896.ref092","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1002\/yea.320111303","article-title":"DOGR1 and DOGR2: two genes from Saccharomyces cerevisiae that confer 2-deoxyglucose resistance when overexpressed","volume":"11","author":"F Randez-Gil","year":"1995","journal-title":"Yeast"},{"issue":"9","key":"pgen.1011896.ref093","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1002\/yea.320100907","article-title":"Molecular characterization of a gene that confers 2-deoxyglucose resistance in yeast","volume":"10","author":"P Sanz","year":"1994","journal-title":"Yeast"},{"key":"pgen.1011896.ref094","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkad1011","article-title":"AlphaFold Protein Structure Database in 2024: providing structure coverage for over 214 million protein sequences","volume":"52","author":"M Varadi","year":"2024","journal-title":"Nucleic Acids Res"},{"issue":"3","key":"pgen.1011896.ref095","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0265422","article-title":"Intrinsically disordered signaling proteins: Essential hub players in the control of stress responses in Saccharomyces cerevisiae","volume":"17","author":"L French-Pacheco","year":"2022","journal-title":"PLoS 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L\u00f5oke","year":"2011","journal-title":"Biotechniques"},{"issue":"6","key":"pgen.1011896.ref099","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1091\/mbc.e08-01-0068","article-title":"Ear1p and Ssh4p are new adaptors of the ubiquitin ligase Rsp5p for cargo ubiquitylation and sorting at multivesicular bodies","volume":"19","author":"S L\u00e9on","year":"2008","journal-title":"Mol Biol Cell"},{"key":"pgen.1011896.ref100","doi-asserted-by":"crossref","first-page":"2685","DOI":"10.1099\/00221287-146-10-2685","article-title":"Mitochondrial respiratory mutants of Saccharomyces cerevisiae accumulate glycogen and readily mobilize it in a glucose-depleted medium","author":"B Enjalbert","year":"2000","journal-title":"Microbiology (Reading)"},{"issue":"14","key":"pgen.1011896.ref101","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler 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