The corn smut fungus uses two different mechanisms to control its cell cycle when it is infecting plants

Bardetti

Chang

Fukada

Müller

Nurse

Osés-Ruiz

Savary

Urban

English

Osés-Ruiz, Míriam

Talbot, Nicholas J

University of East Anglia digital repository

PLANT DISEASECycling in synchronyThe corn smut fungus uses two different mechanisms to control its cellcycle when it is infecting plants.MI´RIAM OSE´S-RUIZ AND NICHOLAS J TALBOTPlant diseases are a major threat to globalfood security (Savary et al., 2019), butwe need to know more about these dis-eases if we want to stop them spreading. Cur-rent disease control strategies are not veryeffective, because of the ability of microbes(such as bacteria or fungi) to develop resistanceto anti-microbial drugs and overcome plantimmunity.Many disease-causing fungi undergo highlycomplex life cycles, with some involving morethan one host plant species, as well as sexualand asexual stages of reproduction (Li et al.,2019). A fascinating example of this complexityis Ustilago maydis, the fungus that causes thedisease called corn smut. For U. maydis to infectcorn plants, two haploid cells belonging to dif-ferent mating types must fuse together on thesurface of a leaf to form an infectious cell knownas an appressorium. This cell can then rupturethe surface and invade the plant’s tissue. Theend result is deformed corn cobs, covered inblack sooty spores – if you have dined on thedelicacy Huitlacoche in a Mexican restaurant,then you’ll have eaten them! However, if you area corn grower, a field of deformed cobs is adisaster.The behavior of U. maydis on a leaf surface isquite remarkable: although infection relies ontwo cells fusing, the nuclei inside these cells donot fuse with each other, so the new cell con-tains two nuclei. This means that the cell mustsomehow control and synchronize two cell cyclesto ensure its survival and development. Now, ineLife, Jose´ Pe´rez-Martı´n and co-workers at theInstitute of Functional and Genomic Biology inSalamanca and Georg August University in Go¨t-tingen – including Paola Bardetti as first author –report how this amazing feat is accomplished(Bardetti et al., 2019).In eukaryotes the cell cycle goes through fourmain stages to produce two identical daughtercells: G1, S (when DNA replication occurs), G2,and M (mitosis; Figure 1A). Progression throughthese stages depends on the activity of a familyof proteins called cyclin-dependent kinases(CDKs) in association with partner proteins calledcyclins. Mechanisms controlling the activity ofCDK1 form the basis of cell cycle regulation(Nurse, 2012): the kinase Wee1 stops the cellcycle by phosphorylating CDK1 and blocking itsactivity, and the phosphatase Cdc25 allows thecycle to start again by dephosphorylating CDK1(Figure 1A).Initial work in model yeast revealed that whencells fuse during mating, synchronization of thecell cycle normally occurs by arresting the cellcycle at the G1 stage (Chang and Herskowitz,1990). In U. maydis, however, the cell cycle isstopped at the G2 stage after DNA replicationhas occurred. Bardetti et al. showed that cellcycle arrest at G2 is triggered by two distinctmechanisms. The first is employed before fusionand involves pheromones released from the twomating cells. The second occurs only after thecells have fused and is necessary to maintainCopyright Ose´s-Ruiz and Talbot.This article is distributed under theterms of the Creative CommonsAttribution License, which permitsunrestricted use and redistributionprovided that the original author andsource are credited.Related research article Bardetti P, Cas-tanheira SM, Valerius O, Braus GH, Pe´rez-Martı´n J. 2019. Cytoplasmic retention anddegradation of a mitotic inducer enableplant infection by a pathogenic fungus.eLife 8:e48943. DOI: 10.7554/eLife.48943Ose´s-Ruiz and Talbot. eLife 2019;8:e52884. DOI: https://doi.org/10.7554/eLife.52884 1 of 3INSIGHTsynchrony of the two nuclei that now occupy thesame cell.Previous work has shown that pheromoneperception triggers G2 cell cycle arrest by activ-ating the Kpp2 signaling cascade (Mu¨ller et al.,2003). Bardetti et al. revealed that Kpp2 inhibitsa protein known as Kap123 from importingCdc25 into the cell nucleus (Figure 1B). Thiscauses Cdc25 levels in the nucleus to decrease,leading to higher levels of inactive CDK1, thuscausing the cell cycle to stop. Activated Kpp2also increases the levels of inactive phosphory-lated CDK1 by repressing the transcription ofthe hls1 gene that normally blocks the activity ofWee1.At this point, as cells of opposite mating typemove towards each other, the Cdc25 proteinswithin their cytoplasm begin to degrade as aresult of Kpp2-dependent phosphorylation. Thisensures that the cell cycle remains stopped.Once the two cells have fused together, theybegin to develop branching filaments that caninvade the plant tissue. The formation of thesefilaments relies on a homeodomain transcrip-tional regulator called b-factor, which keeps thecell cycle arrested at the G2 stage (Urban et al.,1996). Bardetti et al. showed that this sustainedG2 cell cycle arrest involves three separate layersof control on CDK1 activity (Figure 1B). The firstretains Cdc25 in the cytoplasm by binding it to acytoplasmic protein called Bmh1, so it cannotactivate CDK1 in the nucleus; the secondrepresses the transcription of hsl1, leading to anincrease in Wee1 activity; and the third turns ona gene called biz1 which blocks the transcriptionof a protein known as Clb1 that activates CDK1.It is likely that U. maydis employs two differ-ent arrest mechanisms to ensure that cell cycleFigure 1. Cell cycle control during infection by the corn smut fungus Ustilago maydis. (A) Progression throughthe four stages of the eukaryotic cell cycle depends on the activity of cyclin-dependent kinases (CDKs): whenCDK1 is phosphorylated by Wee1 it becomes inactive and stops the cell cycle from progressing. De-phosphorylation by the Cdc25 phosphatase re-activates CDK1, allowing the cell cycle to continue to the nextstage. (B) During infection, U. maydis arrests its cell cycle at the G2 stage using two distinct mechanisms. In thefirst mechanism (left) pheromones released from mating cells prior to fusion activate the Kpp2 signaling cascade,causing the Crk1-Pcl12 complex to phosphorylate the importin protein Kap123 so it can no longer import Cdc25into the nucleus. Activation of Kpp2 also triggers down-regulation of the hls1 gene, which encodes a kinase thatnormally represses Wee1. This leads to increased Wee1 activity and inhibition of CDK1. Once the mating cellshave fused, a second mechanism regulated by a homeodomain transcriptional regulator called b-factor (right)keeps the cell cycle arrested at G2 by: i) activating the DNA damage response (DDR) which causes Cdc25 tobecome phosphorylated and bind to a protein called Bmh1: this interaction ensures that Cdc25 is retained in thecytoplasm and cannot activate CDK1; ii) triggering the transcription of the biz1 gene, which in turn represses thetranscription of the protein Clb1, which is needed to activate CDK1; iii) repressing the transcription of hsl1 genethat leads to an increase in phosphorylated inactive CDK1.Ose´s-Ruiz and Talbot. eLife 2019;8:e52884. DOI: https://doi.org/10.7554/eLife.52884 2 of 3Insight Plant Disease Cycling in synchronycontrol can be rapidly reversed before the cellsfuse, but then maintained after fusion as the fila-ments develop. For example, if the two matingcells on the leaf surface fail to meet each otherthey will likely need to return to their vegetativestate (perhaps to try and mate again!). Thiscould easily be achieved by reversing the phos-phorylation of importin proteins, such asKapp123, which would lead to an increase ofCdc25 in the nucleus. By contrast, once a fila-ment is formed, both mating partners are fullycommitted to each other, and the three layers ofcontrol used to sustain G2 arrest therefore needto be more difficult to reverse. Consistent withthis idea, Bardetti et al. showed that the abilityof U. maydis to infect a corn plant depended onthe b-factor mechanism and not the pheromonemechanism.This work highlights how important cell cycleregulation is for controlling the developmentprocess used by fungi to infect plants. Recentreports suggest that other infectious structuresinvolved in some of the world’s most devastatingcrop diseases also rely on cell cycle check-pointsduring their formation (Ose´s-Ruiz et al., 2017;Fukada and Kubo, 2015). Learning more aboutthe methods used to control the cell cycle inthese systems will be essential for identifyingnew ways to control these diseases.Mı´riam Ose´s-Ruiz is in the Sainsbury Laboratory,University of East Anglia, Norwich, United Kingdomhttps://orcid.org/0000-0002-3989-9071Nicholas J Talbot is in the Sainsbury Laboratory,University of East Anglia, Norwich, United Kingdomnick.talbot@tsl.ac.ukhttps://orcid.org/0000-0001-6434-7757Competing interests: The authors declare that nocompeting interests exist.Published 02 December 2019ReferencesBardetti P, Castanheira SM, Valerius O, Braus GH,Pe´rez-Martı´n J. 2019. Cytoplasmic retention anddegradation of a mitotic inducer enable plant infectionby a pathogenic fungus. eLife 8:e48943. DOI: https://doi.org/10.7554/eLife.48943, PMID: 31621584Chang F, Herskowitz I. 1990. Identification of a genenecessary for cell cycle arrest by a negative growthfactor of yeast: FAR1 is an inhibitor of a G1 cyclin,CLN2. Cell 63:999–1011. DOI: https://doi.org/10.1016/0092-8674(90)90503-7, PMID: 2147873Fukada F, Kubo Y. 2015. Colletotrichum orbiculareregulates cell cycle G1/S progression via a two-component GAP and a GTPase to establish plantinfection. The Plant Cell 27:2530–2544. DOI: https://doi.org/10.1105/tpc.15.00179, PMID: 26320225Li F, Upadhyaya NM, Sperschneider J, Matny O,Nguyen-Phuc H, Mago R, Raley C, Miller ME,Silverstein KAT, Henningsen E, Hirsch CD, Visser B,Pretorius ZA, Steffenson BJ, Schwessinger B, DoddsPN, Figueroa M. 2019. Emergence of the Ug99 lineageof the wheat stem rust pathogen through somatichybridisation. Nature Communications 10:5068.DOI: https://doi.org/10.1038/s41467-019-12927-7,PMID: 31699975Mu¨ller P, Weinzierl G, Brachmann A, Feldbru¨gge M,Kahmann R. 2003. Mating and pathogenicdevelopment of the smut fungus Ustilago maydis areregulated by one mitogen-activated protein kinasecascade. Eukaryotic Cell 2:1187–1199. DOI: https://doi.org/10.1128/EC.2.6.1187-1199.2003,PMID: 14665454Nurse P. 2012. Finding CDK: linking yeast withhumans. Nature Cell Biology 14:776. DOI: https://doi.org/10.1038/ncb2547, PMID: 22854809Ose´s-Ruiz M, Sakulkoo W, Littlejohn GR, Martin-Urdiroz M, Talbot NJ. 2017. Two independent S-phasecheckpoints regulate appressorium-mediated plantinfection by the rice blast fungus Magnaporthe oryzae.PNAS 10:234–244. DOI: https://doi.org/10.1073/pnas.1611307114Savary S, Willocquet L, Pethybridge SJ, Esker P,McRoberts N, Nelson A. 2019. The global burden ofpathogens and pests on major food crops. NatureEcology & Evolution 3:430–439. DOI: https://doi.org/10.1038/s41559-018-0793-y, PMID: 30718852Urban M, Kahmann R, Bo¨lker M. 1996. Identificationof the pheromone response element in Ustilagomaydis. Molecular & General Genetics: MGG 251:31.DOI: https://doi.org/10.1007/bf02174341, PMID: 8628244Ose´s-Ruiz and Talbot. eLife 2019;8:e52884. DOI: https://doi.org/10.7554/eLife.52884 3 of 3Insight Plant Disease Cycling in synchrony

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