Systematic functional analysis of kinases in the fungal pathogen Cryptococcus neoformans

Kyung Tae Lee; Yee Seul So; Dong Hoon Yang; Kwang Woo Jung; Jaeyoung Choi; Dong Gi Lee; Hyojeong Kwon; Juyeong Jang; Li Li Wang; Soohyun Cha; Gena Lee Meyers; Eunji Jeong; Jae Hyung Jin; Yeonseon Lee; Joohyeon Hong; Soohyun Bang; Je Hyun Ji; Goun Park; Hyo Jeong Byun; Sung Woo Park; Young Min Park; Gloria Adedoyin; Taeyup Kim; Anna F. Averette; Jong Soon Choi; Joseph Heitman; Eunji Cheong; Yong Hwan Lee; Yong Sun Bahn

doi:10.1038/ncomms12766

Systematic functional analysis of kinases in the fungal pathogen Cryptococcus neoformans

Kyung Tae Lee, Yee Seul So, Dong Hoon Yang, Kwang Woo Jung, Jaeyoung Choi, Dong Gi Lee, Hyojeong Kwon, Juyeong Jang, Li Li Wang, Soohyun Cha, Gena Lee Meyers, Eunji Jeong, Jae Hyung Jin, Yeonseon Lee, Joohyeon Hong, Soohyun Bang, Je Hyun Ji, Goun Park, Hyo Jeong Byun, Sung Woo ParkYoung Min Park, Gloria Adedoyin, Taeyup Kim, Anna F. Averette, Jong Soon Choi, Joseph Heitman, Eunji Cheong, Yong Hwan Lee, Yong Sun Bahn

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Abstract

Cryptococcus neoformans is the leading cause of death by fungal meningoencephalitis; however, treatment options remain limited. Here we report the construction of 264 signature-tagged gene-deletion strains for 129 putative kinases, and examine their phenotypic traits under 30 distinct in vitro growth conditions and in two different hosts (insect larvae and mice). Clustering analysis of in vitro phenotypic traits indicates that several of these kinases have roles in known signalling pathways, and identifies hitherto uncharacterized signalling cascades. Virulence assays in the insect and mouse models provide evidence of pathogenicity-related roles for 63 kinases involved in the following biological categories: growth and cell cycle, nutrient metabolism, stress response and adaptation, cell signalling, cell polarity and morphology, vacuole trafficking, transfer RNA (tRNA) modification and other functions. Our study provides insights into the pathobiological signalling circuitry of C. neoformans and identifies potential anticryptococcal or antifungal drug targets.

Original language	English
Article number	12766
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12766
Publication status	Published - 2016 Sept 28

Bibliographical note

Funding Information:
We thank Chaeyoon Baek, Hanseul Yang, Taehoon Kim, Sora Lee, Dasom Han, Dong-Yun Choi, Sanghun Kim, Seungyeol Lee, So-Yeon Shin, Aeri Yoo, Yong In Jeong, Yongjae Song, Won Bin Lee, Won Il Chae, Jihwan Lee, Changho Lee, Taehyung Kim and Hanna Na for their technical assistance in constructing the kinase mutant library. This work was supported by National Research Foundation of Korea grants (no. 2010-0029117, 2015R1A2A1A15055687) from MEST, the Strategic Initiative for Microbiomes in Agriculture and Food funded by Ministry of Agriculture, Food and Rural Affairs (916006-2), and the Brain Korea 21 (BK21) PLUS program (to Y.-S.B.). This work was also supported in part by a NIH/NIAID R01-AI050438-10 grant to J.H. and a project fund (C35703) to J.S.C. from Korea Basic Science Institute.

Publisher Copyright:
© 2016 The Author(s).

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/ncomms12766

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Lee, K. T., So, Y. S., Yang, D. H., Jung, K. W., Choi, J., Lee, D. G., Kwon, H., Jang, J., Wang, L. L., Cha, S., Meyers, G. L., Jeong, E., Jin, J. H., Lee, Y., Hong, J., Bang, S., Ji, J. H., Park, G., Byun, H. J., ... Bahn, Y. S. (2016). Systematic functional analysis of kinases in the fungal pathogen Cryptococcus neoformans. Nature communications, 7, [12766]. https://doi.org/10.1038/ncomms12766

@article{4205eab9e9074ac99f38622231c5a541,

title = "Systematic functional analysis of kinases in the fungal pathogen Cryptococcus neoformans",

abstract = "Cryptococcus neoformans is the leading cause of death by fungal meningoencephalitis; however, treatment options remain limited. Here we report the construction of 264 signature-tagged gene-deletion strains for 129 putative kinases, and examine their phenotypic traits under 30 distinct in vitro growth conditions and in two different hosts (insect larvae and mice). Clustering analysis of in vitro phenotypic traits indicates that several of these kinases have roles in known signalling pathways, and identifies hitherto uncharacterized signalling cascades. Virulence assays in the insect and mouse models provide evidence of pathogenicity-related roles for 63 kinases involved in the following biological categories: growth and cell cycle, nutrient metabolism, stress response and adaptation, cell signalling, cell polarity and morphology, vacuole trafficking, transfer RNA (tRNA) modification and other functions. Our study provides insights into the pathobiological signalling circuitry of C. neoformans and identifies potential anticryptococcal or antifungal drug targets.",

author = "Lee, {Kyung Tae} and So, {Yee Seul} and Yang, {Dong Hoon} and Jung, {Kwang Woo} and Jaeyoung Choi and Lee, {Dong Gi} and Hyojeong Kwon and Juyeong Jang and Wang, {Li Li} and Soohyun Cha and Meyers, {Gena Lee} and Eunji Jeong and Jin, {Jae Hyung} and Yeonseon Lee and Joohyeon Hong and Soohyun Bang and Ji, {Je Hyun} and Goun Park and Byun, {Hyo Jeong} and Park, {Sung Woo} and Park, {Young Min} and Gloria Adedoyin and Taeyup Kim and Averette, {Anna F.} and Choi, {Jong Soon} and Joseph Heitman and Eunji Cheong and Lee, {Yong Hwan} and Bahn, {Yong Sun}",

note = "Funding Information: We thank Chaeyoon Baek, Hanseul Yang, Taehoon Kim, Sora Lee, Dasom Han, Dong-Yun Choi, Sanghun Kim, Seungyeol Lee, So-Yeon Shin, Aeri Yoo, Yong In Jeong, Yongjae Song, Won Bin Lee, Won Il Chae, Jihwan Lee, Changho Lee, Taehyung Kim and Hanna Na for their technical assistance in constructing the kinase mutant library. This work was supported by National Research Foundation of Korea grants (no. 2010-0029117, 2015R1A2A1A15055687) from MEST, the Strategic Initiative for Microbiomes in Agriculture and Food funded by Ministry of Agriculture, Food and Rural Affairs (916006-2), and the Brain Korea 21 (BK21) PLUS program (to Y.-S.B.). This work was also supported in part by a NIH/NIAID R01-AI050438-10 grant to J.H. and a project fund (C35703) to J.S.C. from Korea Basic Science Institute. Publisher Copyright: {\textcopyright} 2016 The Author(s).",

year = "2016",

month = sep,

day = "28",

doi = "10.1038/ncomms12766",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

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Lee, KT, So, YS, Yang, DH, Jung, KW, Choi, J, Lee, DG, Kwon, H, Jang, J, Wang, LL, Cha, S, Meyers, GL, Jeong, E, Jin, JH, Lee, Y, Hong, J, Bang, S, Ji, JH, Park, G, Byun, HJ, Park, SW, Park, YM, Adedoyin, G, Kim, T, Averette, AF, Choi, JS, Heitman, J, Cheong, E, Lee, YH & Bahn, YS 2016, 'Systematic functional analysis of kinases in the fungal pathogen Cryptococcus neoformans', Nature communications, vol. 7, 12766. https://doi.org/10.1038/ncomms12766

TY - JOUR

T1 - Systematic functional analysis of kinases in the fungal pathogen Cryptococcus neoformans

AU - Lee, Kyung Tae

AU - So, Yee Seul

AU - Yang, Dong Hoon

AU - Jung, Kwang Woo

AU - Choi, Jaeyoung

AU - Lee, Dong Gi

AU - Kwon, Hyojeong

AU - Jang, Juyeong

AU - Wang, Li Li

AU - Cha, Soohyun

AU - Meyers, Gena Lee

AU - Jeong, Eunji

AU - Jin, Jae Hyung

AU - Lee, Yeonseon

AU - Hong, Joohyeon

AU - Bang, Soohyun

AU - Ji, Je Hyun

AU - Park, Goun

AU - Byun, Hyo Jeong

AU - Park, Sung Woo

AU - Park, Young Min

AU - Adedoyin, Gloria

AU - Kim, Taeyup

AU - Averette, Anna F.

AU - Choi, Jong Soon

AU - Heitman, Joseph

AU - Cheong, Eunji

AU - Lee, Yong Hwan

AU - Bahn, Yong Sun

N1 - Funding Information: We thank Chaeyoon Baek, Hanseul Yang, Taehoon Kim, Sora Lee, Dasom Han, Dong-Yun Choi, Sanghun Kim, Seungyeol Lee, So-Yeon Shin, Aeri Yoo, Yong In Jeong, Yongjae Song, Won Bin Lee, Won Il Chae, Jihwan Lee, Changho Lee, Taehyung Kim and Hanna Na for their technical assistance in constructing the kinase mutant library. This work was supported by National Research Foundation of Korea grants (no. 2010-0029117, 2015R1A2A1A15055687) from MEST, the Strategic Initiative for Microbiomes in Agriculture and Food funded by Ministry of Agriculture, Food and Rural Affairs (916006-2), and the Brain Korea 21 (BK21) PLUS program (to Y.-S.B.). This work was also supported in part by a NIH/NIAID R01-AI050438-10 grant to J.H. and a project fund (C35703) to J.S.C. from Korea Basic Science Institute. Publisher Copyright: © 2016 The Author(s).

PY - 2016/9/28

Y1 - 2016/9/28

N2 - Cryptococcus neoformans is the leading cause of death by fungal meningoencephalitis; however, treatment options remain limited. Here we report the construction of 264 signature-tagged gene-deletion strains for 129 putative kinases, and examine their phenotypic traits under 30 distinct in vitro growth conditions and in two different hosts (insect larvae and mice). Clustering analysis of in vitro phenotypic traits indicates that several of these kinases have roles in known signalling pathways, and identifies hitherto uncharacterized signalling cascades. Virulence assays in the insect and mouse models provide evidence of pathogenicity-related roles for 63 kinases involved in the following biological categories: growth and cell cycle, nutrient metabolism, stress response and adaptation, cell signalling, cell polarity and morphology, vacuole trafficking, transfer RNA (tRNA) modification and other functions. Our study provides insights into the pathobiological signalling circuitry of C. neoformans and identifies potential anticryptococcal or antifungal drug targets.

AB - Cryptococcus neoformans is the leading cause of death by fungal meningoencephalitis; however, treatment options remain limited. Here we report the construction of 264 signature-tagged gene-deletion strains for 129 putative kinases, and examine their phenotypic traits under 30 distinct in vitro growth conditions and in two different hosts (insect larvae and mice). Clustering analysis of in vitro phenotypic traits indicates that several of these kinases have roles in known signalling pathways, and identifies hitherto uncharacterized signalling cascades. Virulence assays in the insect and mouse models provide evidence of pathogenicity-related roles for 63 kinases involved in the following biological categories: growth and cell cycle, nutrient metabolism, stress response and adaptation, cell signalling, cell polarity and morphology, vacuole trafficking, transfer RNA (tRNA) modification and other functions. Our study provides insights into the pathobiological signalling circuitry of C. neoformans and identifies potential anticryptococcal or antifungal drug targets.

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DO - 10.1038/ncomms12766

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Systematic functional analysis of kinases in the fungal pathogen Cryptococcus neoformans

Abstract

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