{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T14:47:35Z","timestamp":1791557255725,"version":"4.3.4"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T00:00:00Z","timestamp":1613001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Fungal Biol."],"abstract":"<jats:p><jats:italic>Aspergillus fumigatus<\/jats:italic> is an opportunistic fungus, capable of causing Invasive Aspergillosis in immunocompromised patients, recently transplanted or undergoing chemotherapy. In the present work, we continued the investigation on <jats:italic>A. fumigatus<\/jats:italic> AtfA-D transcription factors (TFs) characterizing possible genetic and physical interactions between them after normal growth and stressing conditions. We constructed double null mutants for all the possible combinations of \u0394<jats:italic>atfA-, -B, -C<\/jats:italic>, and <jats:italic>-D<\/jats:italic>, and look into their susceptibility to different stressing conditions. Our results indicate complex genetic interactions among these TFs that could impact the response to different kinds of stressful conditions. AtfA-D interactions also affect the <jats:italic>A. fumigatus<\/jats:italic> virulence in <jats:italic>Galleria mellonella<\/jats:italic>. AtfA:GFP is ~97% located in the nucleus while about 20\u201330% of AtfB, -C, and -D:GFP locate into the nucleus in the absence of any stress. Under stressing conditions, AtfB, -C, and -D:GFP translocate to the nucleus about 60\u201380% upon the addition of sorbitol or H<jats:sub>2<\/jats:sub>O<jats:sub>2.<\/jats:sub> These four TFs are also interacting physically forming all the possible combinations of heterodimers. We also identified that AtfA-D physically interact with the MAPK SakA in the absence of any stress and upon osmotic and cell wall stresses. They are involved in the accumulation of trehalose, glycogen and metabolic assimilation of different carbon sources.<\/jats:p>","DOI":"10.3389\/ffunb.2021.632048","type":"journal-article","created":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T14:33:49Z","timestamp":1613226829000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["Genetic Interactions Between Aspergillus fumigatus Basic Leucine Zipper (bZIP) Transcription Factors AtfA, AtfB, AtfC, and AtfD"],"prefix":"10.3389","volume":"2","author":[{"given":"Lilian Pereira","family":"Silva","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Augusta Crivelente","family":"Horta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo Henrique","family":"Goldman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2285","DOI":"10.1091\/mbc.e04-11-0987","article-title":"Specialization of the HOG pathway and its impact on differentiation and virulence of Cryptococcus neoformans","volume":"16","author":"Bahn","year":"2005","journal-title":"Mol. Biol. Cell."},{"key":"B2","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1111\/mmi.13354","article-title":"Mitogen activated protein kinases SakA(HOG1) and MpkC collaborate for Aspergillus fumigatus virulence","volume":"100","author":"Bruder Nascimento","year":"2016","journal-title":"Mol. Microbiol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1093\/mmy\/myw120","article-title":"Aspergillus fumigatus virulence through the lens of transcription factors","volume":"55","author":"Bultman","year":"2017","journal-title":"Med. Mycol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"10352","DOI":"10.1073\/pnas.0601456103","article-title":"A highthroughput gene knockout procedure for Neurospora reveals functions for multiple transcription factors","volume":"103","author":"Colot","year":"2006","journal-title":"Proc. Nat. Acad. Sci. U.S.A."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e02458","DOI":"10.1128\/mBio.02458-20","article-title":"Aspergillus fumigatus G-Protein coupled receptors GprM and GprJ are important for the regulation of the cell wall integrity pathway, secondary metabolite production, and virulence","volume":"11","author":"da Costa Filho","year":"2020","journal-title":"mBio"},{"key":"B6","doi-asserted-by":"publisher","first-page":"261","DOI":"10.3389\/fcimb.2019.00261","article-title":"Stress-activated protein kinases in human fungal pathogens","volume":"9","author":"Day","year":"2019","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e01952","DOI":"10.1128\/mBio.01952-18","article-title":"Protein kinase A and high-osmolarity glycerol response pathways cooperatively control cell wall carbohydrate mobilization in Aspergillus fumigatus","volume":"9","author":"de Assis","year":"2018","journal-title":"mBio"},{"key":"B8","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1186\/s13068-015-0401-1","article-title":"Aspergillus nidulans protein kinase A plays an important role in cellulase production","volume":"8","author":"de Assis","year":"2015","journal-title":"Biotechnol Biofuels"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e103957","DOI":"10.1371\/journal.pone.0103957","article-title":"The involvement of the Mid1\/Cch1\/Yvc1 calcium channels in Aspergillus fumigatus virulence","volume":"9","author":"de Castro","year":"2014","journal-title":"PLoS ONE"},{"key":"B10","doi-asserted-by":"publisher","first-page":"3275","DOI":"10.1111\/febs.13323","article-title":"Osmostress-induced gene expression\u2014a model to understand how stress-activated protein kinases (SAPKs) regulate transcription","volume":"282","author":"de Nadal","year":"2015","journal-title":"FEBS J."},{"key":"B11","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.fgb.2009.10.011","article-title":"cAMP signaling pathway controls glycogen metabolism in Neurospora crassa by regulating the glycogen synthase gene expression and phosphorylation","volume":"47","author":"Freitas","year":"2010","journal-title":"Fungal Genet. Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"475","DOI":"10.4161\/viru.1.6.12985","article-title":"Methods for using Galleria mellonella as a model host to study fungal pathogenesis","volume":"1","author":"Fuchs","year":"2010","journal-title":"Virulence"},{"key":"B13","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1128\/ec.2.1.34-48.2003","article-title":"Expressed sequence tag analysis of the human pathogen Paracoccidioides brasiliensis yeast phase: identification of putative homologues of Candida albicans virulence and pathogenicity genes","volume":"2","author":"Goldman","year":"2003","journal-title":"Eukaryotic Cell"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2756","DOI":"10.1271\/bbb.80001","article-title":"Characterization of bZip-type transcription factor AtfA with reference to stress responses of conidia of Aspergillus nidulans","volume":"72","author":"Hagiwara","year":"2008","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.fgb.2014.10.011","article-title":"The role of AtfA and HOG MAPK pathway in stress tolerance in conidia of Aspergillus fumigatus","volume":"73","author":"Hagiwara","year":"2014","journal-title":"Fungal Genet. Biol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1186\/s12864-016-2689-z","article-title":"Comparative transcriptome analysis revealing dormant conidia and germination associated genes in Aspergillus species: an essential role for AtfA in conidial dormancy","volume":"17","author":"Hagiwara","year":"2016","journal-title":"BMC Genomics"},{"key":"B17","doi-asserted-by":"publisher","first-page":"9534","DOI":"10.1073\/pnas.87.24.9534","article-title":"A bacterial peptide acting as a plant nuclear targeting signal: the amino-terminal portion of Agrobacterium VirD2 protein directs a beta-galactosidase fusion protein into tobacco nuclei","volume":"87","author":"Herrera-Estrella","year":"1990","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B18","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1128\/MMBR.66.2.300-372.2002","article-title":"Osmotic stress signaling and osmoadaptation in yeasts","volume":"66","author":"Hohmann","year":"2002","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1896","DOI":"10.1091\/mbc.e10-11-0914","article-title":"A novel family of dehydrin-like proteins is involved in stress response in the human fungal pathogen Aspergillus fumigatus","volume":"22","author":"Hoi","year":"2011","journal-title":"Mol. Biol. Cell"},{"key":"B20","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/S0065-2660(08)60245-X","article-title":"Meiotic and mitotic recombination in Aspergilllus and its chromosomal aberrations","volume":"19","author":"Kafer","year":"1977","journal-title":"Adv. Genet."},{"key":"B21","doi-asserted-by":"publisher","first-page":"e80572","DOI":"10.1371\/journal.pone.0080572","article-title":"The transcription factors Atf1 and Pcr1 are essential for transcriptional induction of the extracellular maltase Agl1 in fission yeast","volume":"8","author":"Kato","year":"2013","journal-title":"PLoS ONE"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1046\/j.1365-2958.2002.03087.x","article-title":"SakA MAP kinase is involved in stress signal transduction, sexual development and spore viability in Aspergillus nidulans","volume":"45","author":"Kawasaki","year":"2002","journal-title":"Mol. Microbiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1146\/annurev.immunol.16.1.569","article-title":"Dimerization as a regulatory mechanism in signal transduction","volume":"16","author":"Klemm","year":"1998","journal-title":"Annu. Rev. Immunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1111\/j.1365-2958.2011.07581.x","article-title":"Aspergillus nidulans transcription factor AtfA interacts with the MAPK SakA to regulate general stress responses, development and spore functions","volume":"80","author":"Lara-Rojas","year":"2011","journal-title":"Mol. Microbiol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"5160","DOI":"10.1074\/jbc.M608526200","article-title":"Regulation of Schizosaccharomyces pombe Atf1 protein levels by Sty1-mediated phosphorylation and heterodimerization with Pcr1","volume":"282","author":"Lawrence","year":"2007","journal-title":"J. Biol. Chem."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/cmi.12770","article-title":"Aspergillus fumigatus protein phosphatase PpzA is involved in iron assimilation, secondary metabolite production, and virulence","volume":"19","author":"Manfiolli","year":"2017","journal-title":"Cell. Microbiol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"918","DOI":"10.3389\/fmicb.2019.00918","article-title":"Aspergillus fumigatus high osmolarity glycerol mitogen activated protein kinases SakA and MpkC physically interact during osmotic and cell wall stresses","volume":"10","author":"Manfiolli","year":"2019","journal-title":"Front. Microbiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1111\/j.1469-0691.2007.01663.x","article-title":"Role of trehalose in resistance to macrophage killing: study with a tps1\/tps1 trehalose-deficient mutant of Candida albicans","volume":"13","author":"Mart\u00ednez-Esparza","year":"2007","journal-title":"Clin. Microbiol. Infect."},{"key":"B29","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1089\/omi.2010.0046","article-title":"Toward a genomic view of the gene expression program regulated by osmostress in yeast","volume":"14","author":"Mart\u00ednez-Monta\u00f1\u00e9s","year":"2010","journal-title":"OMICS"},{"key":"B30","doi-asserted-by":"publisher","first-page":"2117","DOI":"10.1101\/gad.9.17.2117","article-title":"Pyp1 and Pyp2 PTPases dephosphorylate an osmosensing MAP kinase controlling cell size at division in fission yeast","volume":"9","author":"Millar","year":"1995","journal-title":"Genes Dev."},{"key":"B31","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1210\/edrv.22.2.0428","article-title":"Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions","volume":"22","author":"Pearson","year":"2001","journal-title":"Endocr. Rev."},{"key":"B32","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1016\/j.str.2013.12.017","article-title":"Design of a bZip transcription factor with homo\/heterodimer-induced DNA-binding preference","volume":"22","author":"Pogenberg","year":"2014","journal-title":"Structure"},{"key":"B33","doi-asserted-by":"publisher","first-page":"TE01","DOI":"10.7860\/JCDR\/2016\/17141.7684","article-title":"Pulmonary aspergillosis: what CT can offer before it is too late","volume":"10","author":"Prasad","year":"2016","journal-title":"J. Clin. Diagn. Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1128\/EC.4.8.1343-1352","article-title":"Genomewide identification of Sko1 target promoters reveals a regulatory network that operates in response to osmotic stress in Saccharomyces cerevisiae","volume":"4","author":"Proft","year":"2005","journal-title":"Eukaryotic Cell"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1016\/S1097-2765(02)00557-9","article-title":"Hog1 kinase converts the Sko1-Cyc8-Tup1 repressor complex into an activator that recruits SAGA and SWI\/SNF in response to osmotic stress","volume":"9","author":"Proft","year":"2002","journal-title":"Mol. Cell"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1046\/j.1365-2958.2001.02384.x","article-title":"The Saccharomyces cerevisiae Sko1p transcription factor mediates HOG pathway-dependent osmotic regulation of a set of genes encoding enzymes implicated in protection from oxidative damage","volume":"40","author":"Rep","year":"2001","journal-title":"Mol. Microbiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.fgb.2009.01.002","article-title":"Comparative genomics of MAP kinase and calcium-calcineurin signalling components in plant and human pathogenic fungi","volume":"46","author":"Rispail","year":"2009","journal-title":"Fungal Genet. Biol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"e19272","DOI":"10.7554\/eLife.19272","article-title":"Combinatorial bZIP dimers display complex DNA-binding specificity landscapes","volume":"6","author":"Rodr\u00edguez-Mart\u00ednez","year":"2017","journal-title":"eLife"},{"key":"B39","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1016\/j.fgb.2008.03.009","article-title":"Aspergillus oryzae atfB encodes a transcription factor required for stress tolerance in conidia","volume":"45","author":"Sakamoto","year":"2008","journal-title":"Fungal Genet. Biol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1016\/j.fgb.2009.09.004","article-title":"Aspergillus oryzae atfA controls conidial germination and stress tolerance","volume":"46","author":"Sakamoto","year":"2009","journal-title":"Fungal Genet. Biol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"13635","DOI":"10.1074\/jbc.M117.794339","article-title":"Deciphering the role of the signal- and Sty1 kinase-dependent phosphorylation of the stress-responsive transcription factor Atf1 on gene activation","volume":"292","author":"Salat-Canela","year":"2017","journal-title":"J. Biol. Chem."},{"key":"B42","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1007\/BF00340712","article-title":"High efficiency transformation of intact yeast cells using single stranded nucleic acids as a carrier","volume":"16","author":"Schiestl","year":"1989","journal-title":"Curr. Genet."},{"key":"B43","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1038\/378739a0","article-title":"Cell-cycle control linked to extracellular environment by MAP kinase pathway in fission yeast","volume":"378","author":"Shiozaki","year":"1995","journal-title":"Nature"},{"key":"B44","doi-asserted-by":"publisher","first-page":"e12681","DOI":"10.1111\/cmi.12681","article-title":"Genome-wide transcriptome analysis of Aspergillus fumigatus exposed to osmotic stress reveals regulators of osmotic and cell wall stresses that are SakAHOG1 and MpkC dependent","volume":"19","author":"Silva","year":"2017"},{"key":"B45","doi-asserted-by":"publisher","first-page":"e00818","DOI":"10.1128\/mSphere.00818-20","article-title":"Putative membrane receptors contribute to activation and efficient signaling of mitogen-activated protein kinase cascades during adaptation of aspergillus fumigatus to different stressors and carbon sources","volume":"5","author":"Silva","year":"2020","journal-title":"mSphere"},{"key":"B46","doi-asserted-by":"publisher","first-page":"e00053","DOI":"10.1128\/MMBR.00053-16","article-title":"Central role of the trehalose biosynthesis pathway in the pathogenesis of human fungal infections: opportunities and challenges for therapeutic development","volume":"81","author":"Thammahong","year":"2017","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"B47","doi-asserted-by":"publisher","first-page":"4229","DOI":"10.1016\/j.jmb.2019.03.027","article-title":"Menacing mold: recent advances in Aspergillus pathogenesis and host defense","volume":"431","author":"Tischler","year":"2019","journal-title":"J. Mol. Biol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1016\/j.fgb.2007.09.006","article-title":"The mitogen-activated protein kinase MpkA of Aspergillus fumigatus regulates cell wall signaling and oxidative stress response","volume":"45","author":"Valiante","year":"2008","journal-title":"Fungal Genet. Biol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1016\/j.fgb.2009.08.005","article-title":"The MpkA MAP kinase module regulates cell wall integrity signaling and pyomelanin formation in Aspergillus fumigatus","volume":"46","author":"Valiante","year":"2009","journal-title":"Fungal Genet. Biol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"325","DOI":"10.3389\/fmicb.2015.00325","article-title":"The Aspergillus fumigatus cell wall integrity signaling pathway: drug target, compensatory pathways, and virulence","volume":"6","author":"Valiante","year":"2015","journal-title":"Front. Microbiol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1038\/nrmicro.2017.90","article-title":"Aspergillus fumigatus morphology and dynamic host interactions","volume":"15","author":"van de Veerdonk","year":"2017","journal-title":"Nat. Rev. Microbiol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"71","DOI":"10.3114\/sim0013","article-title":"The effect of natamycin on the transcriptome of conidia of Aspergillus niger","volume":"74","author":"van Leeuwen","year":"2013","journal-title":"Stud. Mycol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"287","DOI":"10.3390\/toxins9090287","article-title":"The fungal bZIP transcription factor AtfB controls virulence-associated processes in Aspergillus parasiticus","volume":"9","author":"Wee","year":"2017","journal-title":"Toxins"},{"key":"B54","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.1101\/gad.10.18.2289","article-title":"The Atf1 transcription factor is a target for the Sty1 stress-activated MAP kinase pathway in fission yeast","volume":"10","author":"Wilkinson","year":"1996","journal-title":"Genes Dev."},{"key":"B55","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1016\/S0959-437X(98)80010-5","article-title":"Combinatorial transcription factors","volume":"8","author":"Wolberger","year":"1998","journal-title":"Curr. Opin. Genet. Dev."}],"container-title":["Frontiers in Fungal Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ffunb.2021.632048\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T14:33:54Z","timestamp":1613226834000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ffunb.2021.632048\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,11]]},"references-count":55,"alternative-id":["10.3389\/ffunb.2021.632048"],"URL":"https:\/\/doi.org\/10.3389\/ffunb.2021.632048","relation":{},"ISSN":["2673-6128"],"issn-type":[{"value":"2673-6128","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,11]]},"article-number":"632048"}}