Genome-wide functional analysis of phosphatases in the pathogenic fungus Cryptococcus neoformans

Jae Hyung Jin; Kyung Tae Lee; Joohyeon Hong; Dongpil Lee; Eun Ha Jang; Jin Young Kim; Yeonseon Lee; Seung Heon Lee; Yee Seul So; Kwang Woo Jung; Dong Gi Lee; Eunji Jeong; Minjae Lee; Yu Byeong Jang; Yeseul Choi; Myung Ha Lee; Ji Seok Kim; Seong Ryong Yu; Jin Tae Choi; Jae Won La; Haneul Choi; Sun Woo Kim; Kyung Jin Seo; Yelin Lee; Eun Jung Thak; Jaeyoung Choi; Anna F. Averette; Yong Hwan Lee; Joseph Heitman; Hyun Ah Kang; Eunji Cheong; Yong Sun Bahn

doi:10.1038/s41467-020-18028-0

Genome-wide functional analysis of phosphatases in the pathogenic fungus Cryptococcus neoformans

Jae Hyung Jin, Kyung Tae Lee, Joohyeon Hong, Dongpil Lee, Eun Ha Jang, Jin Young Kim, Yeonseon Lee, Seung Heon Lee, Yee Seul So, Kwang Woo Jung, Dong Gi Lee, Eunji Jeong, Minjae Lee, Yu Byeong Jang, Yeseul Choi, Myung Ha Lee, Ji Seok Kim, Seong Ryong Yu, Jin Tae Choi, Jae Won LaHaneul Choi, Sun Woo Kim, Kyung Jin Seo, Yelin Lee, Eun Jung Thak, Jaeyoung Choi, Anna F. Averette, Yong Hwan Lee, Joseph Heitman, Hyun Ah Kang, Eunji Cheong, Yong Sun Bahn

Department of Biotechnology

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Abstract

Phosphatases, together with kinases and transcription factors, are key components in cellular signalling networks. Here, we present a systematic functional analysis of the phosphatases in Cryptococcus neoformans, a fungal pathogen that causes life-threatening fungal meningoencephalitis. We analyse 230 signature-tagged mutant strains for 114 putative phosphatases under 30 distinct in vitro growth conditions, revealing at least one function for 60 of these proteins. Large-scale virulence and infectivity assays using insect and mouse models indicate roles in pathogenicity for 31 phosphatases involved in various processes such as thermotolerance, melanin and capsule production, stress responses, O-mannosylation, or retromer function. Notably, phosphatases Xpp1, Ssu72, Siw14, and Sit4 promote blood-brain barrier adhesion and crossing by C. neoformans. Together with our previous systematic studies of transcription factors and kinases, our results provide comprehensive insight into the pathobiological signalling circuitry of C. neoformans.

Original language	English
Article number	4212
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18028-0
Publication status	Published - 2020 Dec 1

Bibliographical note

Funding Information:
This work was supported by the Strategic Initiative for Microbiomes in Agriculture and Food funded by the Ministry of Agriculture, Food and Rural Affairs (grant 916006-2 and 918012-4 to Y.-S.B.) and, in part, by National Research Foundation of Korea grants (grants 2016R1E1A1A01943365 and 2018R1A5A1025077 to Y.-S.B.; 2018R1C1B6009031 to K.-T.L.) from the Ministry of Science and ICT, and Brain Korea 21 (BK21) PLUS programme. This work was also supported by NIH/NIAID R37 MERIT award AI39115-21 and NIH/NIAID RO1 award AI50113-15 to J.H. J.H. is co-director and fellow CIFAR programme Fungal Kingdom: Threats & Opportunities.

Publisher Copyright:
© 2020, 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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Jin, J. H., Lee, K. T., Hong, J., Lee, D., Jang, E. H., Kim, J. Y., Lee, Y., Lee, S. H., So, Y. S., Jung, K. W., Lee, D. G., Jeong, E., Lee, M., Jang, Y. B., Choi, Y., Lee, M. H., Kim, J. S., Yu, S. R., Choi, J. T., ... Bahn, Y. S. (2020). Genome-wide functional analysis of phosphatases in the pathogenic fungus Cryptococcus neoformans. Nature communications, 11(1), [4212]. https://doi.org/10.1038/s41467-020-18028-0

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title = "Genome-wide functional analysis of phosphatases in the pathogenic fungus Cryptococcus neoformans",

abstract = "Phosphatases, together with kinases and transcription factors, are key components in cellular signalling networks. Here, we present a systematic functional analysis of the phosphatases in Cryptococcus neoformans, a fungal pathogen that causes life-threatening fungal meningoencephalitis. We analyse 230 signature-tagged mutant strains for 114 putative phosphatases under 30 distinct in vitro growth conditions, revealing at least one function for 60 of these proteins. Large-scale virulence and infectivity assays using insect and mouse models indicate roles in pathogenicity for 31 phosphatases involved in various processes such as thermotolerance, melanin and capsule production, stress responses, O-mannosylation, or retromer function. Notably, phosphatases Xpp1, Ssu72, Siw14, and Sit4 promote blood-brain barrier adhesion and crossing by C. neoformans. Together with our previous systematic studies of transcription factors and kinases, our results provide comprehensive insight into the pathobiological signalling circuitry of C. neoformans.",

author = "Jin, {Jae Hyung} and Lee, {Kyung Tae} and Joohyeon Hong and Dongpil Lee and Jang, {Eun Ha} and Kim, {Jin Young} and Yeonseon Lee and Lee, {Seung Heon} and So, {Yee Seul} and Jung, {Kwang Woo} and Lee, {Dong Gi} and Eunji Jeong and Minjae Lee and Jang, {Yu Byeong} and Yeseul Choi and Lee, {Myung Ha} and Kim, {Ji Seok} and Yu, {Seong Ryong} and Choi, {Jin Tae} and La, {Jae Won} and Haneul Choi and Kim, {Sun Woo} and Seo, {Kyung Jin} and Yelin Lee and Thak, {Eun Jung} and Jaeyoung Choi and Averette, {Anna F.} and Lee, {Yong Hwan} and Joseph Heitman and Kang, {Hyun Ah} and Eunji Cheong and Bahn, {Yong Sun}",

note = "Funding Information: This work was supported by the Strategic Initiative for Microbiomes in Agriculture and Food funded by the Ministry of Agriculture, Food and Rural Affairs (grant 916006-2 and 918012-4 to Y.-S.B.) and, in part, by National Research Foundation of Korea grants (grants 2016R1E1A1A01943365 and 2018R1A5A1025077 to Y.-S.B.; 2018R1C1B6009031 to K.-T.L.) from the Ministry of Science and ICT, and Brain Korea 21 (BK21) PLUS programme. This work was also supported by NIH/NIAID R37 MERIT award AI39115-21 and NIH/NIAID RO1 award AI50113-15 to J.H. J.H. is co-director and fellow CIFAR programme Fungal Kingdom: Threats & Opportunities. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

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doi = "10.1038/s41467-020-18028-0",

language = "English",

volume = "11",

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Jin, JH, Lee, KT, Hong, J, Lee, D, Jang, EH, Kim, JY, Lee, Y, Lee, SH, So, YS, Jung, KW, Lee, DG, Jeong, E, Lee, M, Jang, YB, Choi, Y, Lee, MH, Kim, JS, Yu, SR, Choi, JT, La, JW, Choi, H, Kim, SW, Seo, KJ, Lee, Y, Thak, EJ, Choi, J, Averette, AF, Lee, YH, Heitman, J, Kang, HA, Cheong, E & Bahn, YS 2020, 'Genome-wide functional analysis of phosphatases in the pathogenic fungus Cryptococcus neoformans', Nature communications, vol. 11, no. 1, 4212. https://doi.org/10.1038/s41467-020-18028-0

TY - JOUR

T1 - Genome-wide functional analysis of phosphatases in the pathogenic fungus Cryptococcus neoformans

AU - Jin, Jae Hyung

AU - Lee, Kyung Tae

AU - Hong, Joohyeon

AU - Lee, Dongpil

AU - Jang, Eun Ha

AU - Kim, Jin Young

AU - Lee, Yeonseon

AU - Lee, Seung Heon

AU - So, Yee Seul

AU - Jung, Kwang Woo

AU - Lee, Dong Gi

AU - Jeong, Eunji

AU - Lee, Minjae

AU - Jang, Yu Byeong

AU - Choi, Yeseul

AU - Lee, Myung Ha

AU - Kim, Ji Seok

AU - Yu, Seong Ryong

AU - Choi, Jin Tae

AU - La, Jae Won

AU - Choi, Haneul

AU - Kim, Sun Woo

AU - Seo, Kyung Jin

AU - Lee, Yelin

AU - Thak, Eun Jung

AU - Choi, Jaeyoung

AU - Averette, Anna F.

AU - Lee, Yong Hwan

AU - Heitman, Joseph

AU - Kang, Hyun Ah

AU - Cheong, Eunji

AU - Bahn, Yong Sun

N1 - Funding Information: This work was supported by the Strategic Initiative for Microbiomes in Agriculture and Food funded by the Ministry of Agriculture, Food and Rural Affairs (grant 916006-2 and 918012-4 to Y.-S.B.) and, in part, by National Research Foundation of Korea grants (grants 2016R1E1A1A01943365 and 2018R1A5A1025077 to Y.-S.B.; 2018R1C1B6009031 to K.-T.L.) from the Ministry of Science and ICT, and Brain Korea 21 (BK21) PLUS programme. This work was also supported by NIH/NIAID R37 MERIT award AI39115-21 and NIH/NIAID RO1 award AI50113-15 to J.H. J.H. is co-director and fellow CIFAR programme Fungal Kingdom: Threats & Opportunities. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Phosphatases, together with kinases and transcription factors, are key components in cellular signalling networks. Here, we present a systematic functional analysis of the phosphatases in Cryptococcus neoformans, a fungal pathogen that causes life-threatening fungal meningoencephalitis. We analyse 230 signature-tagged mutant strains for 114 putative phosphatases under 30 distinct in vitro growth conditions, revealing at least one function for 60 of these proteins. Large-scale virulence and infectivity assays using insect and mouse models indicate roles in pathogenicity for 31 phosphatases involved in various processes such as thermotolerance, melanin and capsule production, stress responses, O-mannosylation, or retromer function. Notably, phosphatases Xpp1, Ssu72, Siw14, and Sit4 promote blood-brain barrier adhesion and crossing by C. neoformans. Together with our previous systematic studies of transcription factors and kinases, our results provide comprehensive insight into the pathobiological signalling circuitry of C. neoformans.

AB - Phosphatases, together with kinases and transcription factors, are key components in cellular signalling networks. Here, we present a systematic functional analysis of the phosphatases in Cryptococcus neoformans, a fungal pathogen that causes life-threatening fungal meningoencephalitis. We analyse 230 signature-tagged mutant strains for 114 putative phosphatases under 30 distinct in vitro growth conditions, revealing at least one function for 60 of these proteins. Large-scale virulence and infectivity assays using insect and mouse models indicate roles in pathogenicity for 31 phosphatases involved in various processes such as thermotolerance, melanin and capsule production, stress responses, O-mannosylation, or retromer function. Notably, phosphatases Xpp1, Ssu72, Siw14, and Sit4 promote blood-brain barrier adhesion and crossing by C. neoformans. Together with our previous systematic studies of transcription factors and kinases, our results provide comprehensive insight into the pathobiological signalling circuitry of C. neoformans.

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DO - 10.1038/s41467-020-18028-0

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JO - Nature Communications

JF - Nature Communications

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ER -

Genome-wide functional analysis of phosphatases in the pathogenic fungus Cryptococcus neoformans

Abstract

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