{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T23:34:10Z","timestamp":1784590450483,"version":"3.55.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2024,1,27]],"date-time":"2024-01-27T00:00:00Z","timestamp":1706313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"publisher","award":["AI039115-26"],"award-info":[{"award-number":["AI039115-26"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"publisher","award":["AI050113-19"],"award-info":[{"award-number":["AI050113-19"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"publisher","award":["AI170543-02"],"award-info":[{"award-number":["AI170543-02"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"publisher","award":["AI33654-06"],"award-info":[{"award-number":["AI33654-06"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006967","name":"Duke University Center for AIDS Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006967","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,3,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Adaptation to external environmental challenges at the cellular level requires rapid responses and involves relay of information to the nucleus to drive key gene expression changes through downstream transcription factors. Here, we describe an alternative route of adaptation through a direct role for cellular signaling components in governing gene expression via RNA interference-mediated small RNA production. Calcium\u2013calcineurin signaling is a highly conserved signaling cascade that plays central roles in stress adaptation and virulence of eukaryotic pathogens, including the human fungal pathogen Cryptococcus neoformans. Upon activation in C. neoformans, calcineurin localizes to P-bodies, membraneless organelles that are also the site for RNA processing. Here, we studied the role of calcineurin and its substrates in RNAi-mediated transgene silencing. Our results reveal that calcineurin regulates both the onset and the reversion of transgene silencing. We found that some calcineurin substrates that localize to P-bodies also regulate transgene silencing but in opposing directions. Small RNA sequencing in mutants lacking calcineurin or its targets revealed a role for calcineurin in small RNA production. Interestingly, the impact of calcineurin and its substrates was found to be different in genome-wide analysis, suggesting that calcineurin may regulate small RNA production in C. neoformans through additional pathways. Overall, these findings define a mechanism by which signaling machinery induced by external stimuli can directly alter gene expression to accelerate adaptative responses and contribute to genome defense.<\/jats:p>","DOI":"10.1093\/genetics\/iyae010","type":"journal-article","created":{"date-parts":[[2024,1,27]],"date-time":"2024-01-27T09:51:50Z","timestamp":1706349110000},"source":"Crossref","is-referenced-by-count":8,"title":["Calcineurin contributes to RNAi-mediated transgene silencing and small interfering RNA production in the human fungal pathogen\n                    <i>Cryptococcus neoformans<\/i>"],"prefix":"10.1093","volume":"226","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2650-9035","authenticated-orcid":false,"given":"Vikas","family":"Yadav","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center , Durham, NC 27710 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riya","family":"Mohan","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center , Durham, NC 27710 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2895-1153","authenticated-orcid":false,"given":"Sheng","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center , Durham, NC 27710 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6369-5995","authenticated-orcid":false,"given":"Joseph","family":"Heitman","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center , Durham, NC 27710 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,1,27]]},"reference":[{"issue":"7","key":"2024091717023022900_iyae010-B1","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1038\/nrg2364","article-title":"The art and design of genetic screens: RNA interference","volume":"9","author":"Boutros","year":"2008","journal-title":"Nat Rev Genet"},{"issue":"2","key":"2024091717023022900_iyae010-B2","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/sj.hdy.6800789","article-title":"RNAi: a defensive RNA-silencing against viruses and transposable elements","volume":"96","author":"Buchon","year":"2006","journal-title":"Heredity (Edinb)."},{"issue":"7","key":"2024091717023022900_iyae010-B3","doi-asserted-by":"publisher","first-page":"2235","DOI":"10.1534\/g3.119.400330","article-title":"A non-dicer RNase III and four other novel factors required for RNAi-mediated transposon suppression in the human pathogenic yeast Cryptococcus neoformans","volume":"9","author":"Burke","year":"2019","journal-title":"G3 (Bethesda)"},{"issue":"7519","key":"2024091717023022900_iyae010-B4","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1038\/nature13575","article-title":"Antifungal drug resistance evoked via RNAi-dependent epimutations","volume":"513","author":"Calo","year":"2014","journal-title":"Nature"},{"issue":"2","key":"2024091717023022900_iyae010-B5","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/nrg3355","article-title":"RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond","volume":"14","author":"Castel","year":"2013","journal-title":"Nat Rev Genet"},{"issue":"2","key":"2024091717023022900_iyae010-B6","doi-asserted-by":"publisher","first-page":"e1007957","DOI":"10.1371\/journal.pgen.1007957","article-title":"Broad antifungal resistance mediated by RNAi-dependent epimutation in the basal human fungal pathogen Mucor circinelloides","volume":"15","author":"Chang","year":"2019","journal-title":"PLoS Genet."},{"issue":"6","key":"2024091717023022900_iyae010-B7","doi-asserted-by":"publisher","first-page":"02579-19","DOI":"10.1128\/mBio.02579-19","article-title":"Drug-resistant epimutants exhibit organ-specific stability and induction during murine infections caused by the human fungal pathogen Mucor circinelloides","volume":"10","author":"Chang","year":"2019","journal-title":"mBio"},{"issue":"4","key":"2024091717023022900_iyae010-B8","doi-asserted-by":"publisher","first-page":"e1006667","DOI":"10.1371\/journal.pgen.1006667","article-title":"Elucidation of the calcineurin-Crz1 stress response transcriptional network in the human fungal pathogen Cryptococcus neoformans","volume":"13","author":"Chow","year":"2017","journal-title":"PLoS Genet."},{"issue":"6732","key":"2024091717023022900_iyae010-B9","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1038\/20215","article-title":"Gene silencing in Neurospora crassa requires a protein homologous to RNA-dependent RNA polymerase","volume":"399","author":"Cogoni","year":"1999","journal-title":"Nature"},{"issue":"5","key":"2024091717023022900_iyae010-B10","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1093\/emboj\/20.5.1020","article-title":"Calcineurin is required for hyphal elongation during mating and haploid fruiting in Cryptococcus neoformans","volume":"20","author":"Cruz","year":"2001","journal-title":"EMBO J"},{"issue":"5","key":"2024091717023022900_iyae010-B11","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1016\/j.cell.2013.01.046","article-title":"Stalled spliceosomes are a signal for RNAi-mediated genome defense","volume":"152","author":"Dumesic","year":"2013","journal-title":"Cell"},{"issue":"3","key":"2024091717023022900_iyae010-B12","doi-asserted-by":"publisher","first-page":"e1005868","DOI":"10.1371\/journal.pgen.1005868","article-title":"Gene network polymorphism illuminates loss and retention of novel RNAi silencing components in the Cryptococcus pathogenic species complex","volume":"12","author":"Feretzaki","year":"2016","journal-title":"PLoS Genet."},{"issue":"5859","key":"2024091717023022900_iyae010-B13","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1126\/science.1150944","article-title":"Heterochromatin and RNAi are required to establish CENP-A chromatin at centromeres","volume":"319","author":"Folco","year":"2008","journal-title":"Science"},{"issue":"4","key":"2024091717023022900_iyae010-B14","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1046\/j.1365-2958.2001.02295.x","article-title":"Calcineurin regulatory subunit is essential for virulence and mediates interactions with FKBP12-FK506 in Cryptococcus neoformans","volume":"39","author":"Fox","year":"2001","journal-title":"Mol Microbiol"},{"issue":"6","key":"2024091717023022900_iyae010-B15","doi-asserted-by":"publisher","first-page":"C2213","DOI":"10.1152\/ajpcell.00139.2005","article-title":"Nuclear translocation of calcineurin A\u03b2 but not calcineurin A\u03b1 by platelet-derived growth factor in rat aortic smooth muscle","volume":"292","author":"Jabr","year":"2007","journal-title":"Am J Physiol Cell Physiol"},{"issue":"12","key":"2024091717023022900_iyae010-B16","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1016\/j.fgb.2010.10.005","article-title":"Characterizing the role of RNA silencing components in Cryptococcus neoformans","volume":"47","author":"Janbon","year":"2010","journal-title":"Fungal Genet Biol"},{"key":"2024091717023022900_iyae010-B17","author":"Kalem","year":"2022"},{"issue":"1","key":"2024091717023022900_iyae010-B18","doi-asserted-by":"publisher","first-page":"e03225-20","DOI":"10.1128\/mBio.03225-20","article-title":"Puf4 mediates post-transcriptional regulation of cell wall biosynthesis and caspofungin resistance in Cryptococcus neoformans","volume":"12","author":"Kalem","year":"2021","journal-title":"mBio"},{"issue":"11","key":"2024091717023022900_iyae010-B19","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1128\/EC.05087-11","article-title":"Calcineurin colocalizes with P-bodies and stress granules during thermal stress in Cryptococcus neoformans","volume":"10","author":"Kozubowski","year":"2011","journal-title":"Eukaryot Cell"},{"issue":"24","key":"2024091717023022900_iyae010-B20","doi-asserted-by":"publisher","first-page":"9348","DOI":"10.3390\/ijms21249348","article-title":"The evolutionary significance of RNAi in the fungal kingdom","volume":"21","author":"Lax","year":"2020","journal-title":"Int J Mol Sci"},{"issue":"12","key":"2024091717023022900_iyae010-B21","doi-asserted-by":"publisher","first-page":"7383","DOI":"10.1128\/MCB.18.12.7383","article-title":"Pbp1p, a factor interacting with Saccharomyces cerevisiae poly(A)-binding protein, regulates polyadenylation","volume":"18","author":"Mangus","year":"1998","journal-title":"Mol Cell Biol"},{"issue":"26","key":"2024091717023022900_iyae010-B22","doi-asserted-by":"publisher","first-page":"5950","DOI":"10.1016\/j.febslet.2005.08.016","article-title":"RNA silencing in fungi: mechanisms and applications","volume":"579","author":"Nakayashiki","year":"2005","journal-title":"FEBS Lett"},{"issue":"6","key":"2024091717023022900_iyae010-B23","doi-asserted-by":"publisher","first-page":"FUNK-0008-2016","DOI":"10.1128\/microbiolspec.FUNK-0008-2016","article-title":"RNA interference in fungi: retention and loss","volume":"4","author":"Nicol\u00e1s","year":"2016","journal-title":"Microbiol Spectr"},{"issue":"1513","key":"2024091717023022900_iyae010-B24","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1098\/rstb.2008.0168","article-title":"The evolution of RNAi as a defence against viruses and transposable elements","volume":"364","author":"Obbard","year":"2009","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"issue":"10","key":"2024091717023022900_iyae010-B25","doi-asserted-by":"publisher","first-page":"2576","DOI":"10.1093\/emboj\/16.10.2576","article-title":"Calcineurin is required for virulence of Cryptococcus neoformans","volume":"16","author":"Odom","year":"1997","journal-title":"EMBO J"},{"issue":"9","key":"2024091717023022900_iyae010-B26","doi-asserted-by":"publisher","first-page":"e1005873","DOI":"10.1371\/journal.ppat.1005873","article-title":"Calcineurin targets involved in stress survival and fungal virulence","volume":"12","author":"Park","year":"2016","journal-title":"PLoS Pathog."},{"issue":"4","key":"2024091717023022900_iyae010-B27","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/j.chom.2019.08.004","article-title":"Calcium-calmodulin-calcineurin signaling: a globally conserved virulence cascade in eukaryotic microbial pathogens","volume":"26","author":"Park","year":"2019","journal-title":"Cell Host Microbe"},{"issue":"12","key":"2024091717023022900_iyae010-B28","doi-asserted-by":"publisher","first-page":"3305","DOI":"10.1128\/jcm.31.12.3305-3309.1993","article-title":"Karyotyping of Cryptococcus neoformans as an epidemiological tool","volume":"31","author":"Perfect","year":"1993","journal-title":"J Clin Microbiol"},{"issue":"8","key":"2024091717023022900_iyae010-B29","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1038\/s41564-022-01183-z","article-title":"Uncontrolled transposition following RNAi loss causes hypermutation and antifungal drug resistance in clinical isolates of Cryptococcus neoformans","volume":"7","author":"Priest","year":"2022","journal-title":"Nat Microbiol"},{"issue":"12","key":"2024091717023022900_iyae010-B30","doi-asserted-by":"publisher","first-page":"1748","DOI":"10.1016\/S1473-3099(22)00499-6","article-title":"The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis","volume":"22","author":"Rajasingham","year":"2022","journal-title":"Lancet Infect Dis"},{"issue":"8","key":"2024091717023022900_iyae010-B31","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/S1473-3099(17)30243-8","article-title":"Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis","volume":"17","author":"Rajasingham","year":"2017","journal-title":"Lancet Infect Dis"},{"issue":"7","key":"2024091717023022900_iyae010-B32","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.1261\/rna.955508","article-title":"S. cerevisiae Vts1p induces deadenylation-dependent transcript degradation and interacts with the Ccr4p-Pop2p-Not deadenylase complex","volume":"14","author":"Rendl","year":"2008","journal-title":"RNA"},{"issue":"4","key":"2024091717023022900_iyae010-B33","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1152\/physrev.2000.80.4.1483","article-title":"Calcineurin: form and function","volume":"80","author":"Rusnak","year":"2000","journal-title":"Physiol Rev"},{"issue":"10","key":"2024091717023022900_iyae010-B34","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1016\/j.tree.2008.06.005","article-title":"Origins and evolution of eukaryotic RNA interference","volume":"23","author":"Shabalina","year":"2008","journal-title":"Trends Ecol Evol"},{"issue":"6589","key":"2024091717023022900_iyae010-B35","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1038\/382370a0","article-title":"Role of kinases and the phosphatase calcineurin in the nuclear shuttling of transcription factor NF-AT4","volume":"382","author":"Shibasaki","year":"1996","journal-title":"Nature"},{"issue":"1","key":"2024091717023022900_iyae010-B36","doi-asserted-by":"publisher","first-page":"e75","DOI":"10.1002\/cpmc.75","article-title":"Cryptococcus neoformans mating and genetic crosses","volume":"53","author":"Sun","year":"2019","journal-title":"Curr Protoc Microbiol"},{"issue":"8","key":"2024091717023022900_iyae010-B37","doi-asserted-by":"publisher","first-page":"jcs260353","DOI":"10.1242\/jcs.260353","article-title":"Calcineurin associates with centrosomes and regulates cilia length maintenance","volume":"136","author":"Tsekitsidou","year":"2023","journal-title":"J Cell Sci"},{"issue":"1","key":"2024091717023022900_iyae010-B38","doi-asserted-by":"publisher","first-page":"119366","DOI":"10.1016\/j.bbamcr.2022.119366","article-title":"A cellular atlas of calcineurin signaling","volume":"1870","author":"Ulengin-Talkish","year":"2023","journal-title":"Biochim Biophys Acta Mol Cell Res"},{"issue":"2","key":"2024091717023022900_iyae010-B39","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1023\/A:1022815931524","article-title":"RNA interference is required for normal centromere function in fission yeast","volume":"11","author":"Volpe","year":"2003","journal-title":"Chromosome Res"},{"issue":"9","key":"2024091717023022900_iyae010-B40","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1016\/j.chom.2021.07.003","article-title":"A calmodulin-binding transcription factor links calcium signaling to antiviral RNAi defense in plants","volume":"29","author":"Wang","year":"2021","journal-title":"Cell Host Microbe"},{"issue":"22","key":"2024091717023022900_iyae010-B41","doi-asserted-by":"publisher","first-page":"2566","DOI":"10.1101\/gad.1970910","article-title":"Sex-induced silencing defends the genome of Cryptococcus neoformans via RNAi","volume":"24","author":"Wang","year":"2010","journal-title":"Genes Dev"},{"issue":"8","key":"2024091717023022900_iyae010-B42","doi-asserted-by":"publisher","first-page":"e1002885","DOI":"10.1371\/journal.pgen.1002885","article-title":"Transgene induced co-suppression during vegetative growth in Cryptococcus neoformans","volume":"8","author":"Wang","year":"2012","journal-title":"PLoS Genet."},{"issue":"2","key":"2024091717023022900_iyae010-B43","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1016\/j.molcel.2020.06.029","article-title":"Systematic discovery of short linear motifs decodes calcineurin phosphatase signaling","volume":"79","author":"Wigington","year":"2020","journal-title":"Mol Cell"},{"key":"2024091717023022900_iyae010-B44","doi-asserted-by":"publisher","author":"Yadav","year":"2024","DOI":"10.6084\/m9.figshare.24975069.v1"},{"issue":"7","key":"2024091717023022900_iyae010-B45","doi-asserted-by":"publisher","first-page":"e1011445","DOI":"10.1371\/journal.ppat.1011445","article-title":"Calcineurin: the Achilles\u2019 heel of fungal pathogens","volume":"19","author":"Yadav","year":"2023","journal-title":"PLoS Pathog"},{"issue":"12","key":"2024091717023022900_iyae010-B46","doi-asserted-by":"publisher","first-page":"3108","DOI":"10.1073\/pnas.1713725115","article-title":"RNAi is a critical determinant of centromere evolution in closely related fungi","volume":"115","author":"Yadav","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"14","key":"2024091717023022900_iyae010-B47","doi-asserted-by":"publisher","first-page":"7917","DOI":"10.1073\/pnas.1918659117","article-title":"Centromere scission drives chromosome shuffling and reproductive isolation","volume":"117","author":"Yadav","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"2024091717023022900_iyae010-B48","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1146\/annurev-micro-020518-120210","article-title":"Life cycle of Cryptococcus neoformans","volume":"73","author":"Zhao","year":"2019","journal-title":"Annu Rev Microbiol"}],"container-title":["GENETICS"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/genetics\/advance-article-pdf\/doi\/10.1093\/genetics\/iyae010\/56657825\/iyae010.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/genetics\/article-pdf\/226\/3\/iyae010\/59153444\/iyae010.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/genetics\/article-pdf\/226\/3\/iyae010\/59153444\/iyae010.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,17]],"date-time":"2024-09-17T13:03:00Z","timestamp":1726578180000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/genetics\/article\/doi\/10.1093\/genetics\/iyae010\/7590558"}},"subtitle":[],"editor":[{"given":"A","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,1,27]]},"references-count":48,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,1,27]]},"published-print":{"date-parts":[[2024,3,6]]}},"URL":"https:\/\/doi.org\/10.1093\/genetics\/iyae010","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.07.25.550548","asserted-by":"object"}]},"ISSN":["1943-2631"],"issn-type":[{"value":"1943-2631","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,3]]},"published":{"date-parts":[[2024,1,27]]},"article-number":"iyae010"}}