Functional Analysis of the Kinome Reveals Hrr25 As a Regulator of Antifungal Susceptibility

Overview

Journal iScience

Publisher Cell Press

Date 2022 Jun 6

PMID 35663022

Authors

Yunjin Lee

Sean D Liston

Dongyeob Lee

Nicole Robbins

Leah E Cowen

Affiliations

Soon will be listed here.

Abstract

is a leading cause of death due to systemic fungal infections. Poor patient outcomes are attributable to the limited number of antifungal classes and the increasing prevalence of drug resistance. Protein kinases have emerged as rewarding targets in the development of drugs for diverse diseases, yet kinases remain untapped in the quest for new antifungals. Here, we performed a comprehensive analysis of the kinome to identify genes for which loss-of-function confers hypersensitivity to the two most widely deployed antifungals, echinocandins and azoles. Through this analysis, we found a role for the casein kinase 1 (CK1) homologue Hrr25 in regulating tolerance to both antifungals as well as target-mediated echinocandin resistance. Follow-up investigations established that Hrr25 regulates these responses through its interaction with the SBF transcription factor. Thus, we provide insights into the circuitry governing cellular responses to antifungals and implicate Hrr25 as a key mediator of drug resistance.

Citing Articles

Echinocandin Adaptation in Is Accompanied by Altered Chromatin Accessibility at Gene Promoters and by Cell Wall Remodeling.

Sah S, Yadav A, Stahl T, Hayes J, Bulger M, Rustchenko E J Fungi (Basel). 2025; 11(2).

PMID: 39997404 PMC: 11856910. DOI: 10.3390/jof11020110.

Chemoproteomic Profiling of for Characterization of Anti-fungal Kinase Inhibitors.

Shirley D, Nandakumar M, Cabrera A, Yiu B, Puumala E, Liu Z bioRxiv. 2025; .

PMID: 39829896 PMC: 11741263. DOI: 10.1101/2025.01.10.632200.

Systematic analysis of the kinome reveals environmentally contingent protein kinase-mediated regulation of filamentation and biofilm formation and .

Kramara J, Kim M, Ollinger T, Ristow L, Wakade R, Zarnowski R mBio. 2024; 15(8):e0124924.

PMID: 38949302 PMC: 11323567. DOI: 10.1128/mbio.01249-24.

The putative prenyltransferase Nus1 is required for filamentation in the human fungal pathogen Candida albicans.

Farheen A, Case N, MacAlpine J, Fu C, Robbins N, Cowen L G3 (Bethesda). 2024; 14(8).

PMID: 38874344 PMC: 11304969. DOI: 10.1093/g3journal/jkae124.

Molecular mechanisms governing antifungal drug resistance.

Lee Y, Robbins N, Cowen L NPJ Antimicrob Resist. 2024; 1(1):5.

PMID: 38686214 PMC: 11057204. DOI: 10.1038/s44259-023-00007-2.

References

van Leeuwen J, Pons C, Mellor J, Yamaguchi T, Friesen H, Koschwanez J . Exploring genetic suppression interactions on a global scale. Science. 2016; 354(6312). PMC: 5562937. DOI: 10.1126/science.aag0839. View

Liu Z, Myers L . Mediator Tail Module Is Required for Tac1-Activated Expression and Azole Resistance in Candida albicans. Antimicrob Agents Chemother. 2017; 61(11). PMC: 5655045. DOI: 10.1128/AAC.01342-17. View

Shekhar-Guturja T, Aji Tebung W, Mount H, Liu N, Kohler J, Whiteway M . Beauvericin Potentiates Azole Activity via Inhibition of Multidrug Efflux, Blocks Candida albicans Morphogenesis, and Is Effluxed via Yor1 and Circuitry Controlled by Zcf29. Antimicrob Agents Chemother. 2016; 60(12):7468-7480. PMC: 5119031. DOI: 10.1128/AAC.01959-16. View

Lee J, Robbins N, Xie J, Ketela T, Cowen L . Functional Genomic Analysis of Candida albicans Adherence Reveals a Key Role for the Arp2/3 Complex in Cell Wall Remodelling and Biofilm Formation. PLoS Genet. 2016; 12(11):e1006452. PMC: 5147769. DOI: 10.1371/journal.pgen.1006452. View

Wang C, Zhang S, Hou R, Zhao Z, Zheng Q, Xu Q . Functional analysis of the kinome of the wheat scab fungus Fusarium graminearum. PLoS Pathog. 2012; 7(12):e1002460. PMC: 3245316. DOI: 10.1371/journal.ppat.1002460. View

Levin D . Regulation of cell wall biogenesis in Saccharomyces cerevisiae: the cell wall integrity signaling pathway. Genetics. 2011; 189(4):1145-75. PMC: 3241422. DOI: 10.1534/genetics.111.128264. View

Noble S, Johnson A . Strains and strategies for large-scale gene deletion studies of the diploid human fungal pathogen Candida albicans. Eukaryot Cell. 2005; 4(2):298-309. PMC: 549318. DOI: 10.1128/EC.4.2.298-309.2005. View

Xie J, Qin L, Miao Z, Grys B, De La Cruz Diaz J, Ting K . The Candida albicans transcription factor Cas5 couples stress responses, drug resistance and cell cycle regulation. Nat Commun. 2017; 8(1):499. PMC: 5593949. DOI: 10.1038/s41467-017-00547-y. View

Bimbo A, Jia Y, Poh S, Karuturi R, Den Elzen N, Peng X . Systematic deletion analysis of fission yeast protein kinases. Eukaryot Cell. 2005; 4(4):799-813. PMC: 1087820. DOI: 10.1128/EC.4.4.799-813.2005. View

10.

Wisplinghoff H, Bischoff T, Tallent S, Seifert H, Wenzel R, Edmond M . Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004; 39(3):309-17. DOI: 10.1086/421946. View

11.

Pfaller M, Diekema D, Turnidge J, Castanheira M, Jones R . Twenty Years of the SENTRY Antifungal Surveillance Program: Results for Species From 1997-2016. Open Forum Infect Dis. 2019; 6(Suppl 1):S79-S94. PMC: 6419901. DOI: 10.1093/ofid/ofy358. View

12.

Pfaller M, Diekema D . Epidemiology of invasive mycoses in North America. Crit Rev Microbiol. 2010; 36(1):1-53. DOI: 10.3109/10408410903241444. View

13.

Roncero C, Duran A . Effect of Calcofluor white and Congo red on fungal cell wall morphogenesis: in vivo activation of chitin polymerization. J Bacteriol. 1985; 163(3):1180-5. PMC: 219256. DOI: 10.1128/jb.163.3.1180-1185.1985. View

14.

Laemmli U . Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970; 227(5259):680-5. DOI: 10.1038/227680a0. View

15.

Enoch D, Yang H, Aliyu S, Micallef C . The Changing Epidemiology of Invasive Fungal Infections. Methods Mol Biol. 2016; 1508:17-65. DOI: 10.1007/978-1-4939-6515-1_2. View

16.

Bar-Yosef H, Gildor T, Ramirez-Zavala B, Schmauch C, Weissman Z, Pinsky M . A Global Analysis of Kinase Function in Hyphal Morphogenesis Reveals a Role for the Endocytosis Regulator Akl1. Front Cell Infect Microbiol. 2018; 8:17. PMC: 5809406. DOI: 10.3389/fcimb.2018.00017. View

17.

Ramirez-Zavala B, Weyler M, Gildor T, Schmauch C, Kornitzer D, Arkowitz R . Activation of the Cph1-dependent MAP kinase signaling pathway induces white-opaque switching in Candida albicans. PLoS Pathog. 2013; 9(10):e1003696. PMC: 3795047. DOI: 10.1371/journal.ppat.1003696. View

18.

Iyer V, Horak C, Scafe C, Botstein D, Snyder M, Brown P . Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF. Nature. 2001; 409(6819):533-8. DOI: 10.1038/35054095. View

19.

Caplan T, Polvi E, Xie J, Buckhalter S, Leach M, Robbins N . Functional Genomic Screening Reveals Core Modulators of Echinocandin Stress Responses in Candida albicans. Cell Rep. 2018; 23(8):2292-2298. DOI: 10.1016/j.celrep.2018.04.084. View

20.

Berman J, Krysan D . Drug resistance and tolerance in fungi. Nat Rev Microbiol. 2020; 18(6):319-331. PMC: 7231573. DOI: 10.1038/s41579-019-0322-2. View