Genome-wide analysis of the regulation of Cu metabolism in Cryptococcus neoformans
Sarela Garcia-Santamarina
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
These authors contributed equally to this work.
Search for more papers by this authorRichard A. Festa
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
These authors contributed equally to this work.
Search for more papers by this authorAaron D. Smith
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
These authors contributed equally to this work.
Search for more papers by this authorChen-Hsin Yu
Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
These authors contributed equally to this work.
Search for more papers by this authorCorinna Probst
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
Search for more papers by this authorChen Ding
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
Search for more papers by this authorChristina M. Homer
Department of Biochemistry and Biophysics, UCSF, San Francisco, CA, USA
Search for more papers by this authorJun Yin
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
Search for more papers by this authorJames P. Noonan
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
Search for more papers by this authorHiten Madhani
Department of Biochemistry and Biophysics, UCSF, San Francisco, CA, USA
Search for more papers by this authorJohn R. Perfect
Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
Search for more papers by this authorCorresponding Author
Dennis J. Thiele
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA
Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA
For correspondence. E-mail [email protected]; Tel. 919-684-5776; Fax 919-668-6044.Search for more papers by this authorSarela Garcia-Santamarina
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
These authors contributed equally to this work.
Search for more papers by this authorRichard A. Festa
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
These authors contributed equally to this work.
Search for more papers by this authorAaron D. Smith
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
These authors contributed equally to this work.
Search for more papers by this authorChen-Hsin Yu
Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
These authors contributed equally to this work.
Search for more papers by this authorCorinna Probst
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
Search for more papers by this authorChen Ding
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
Search for more papers by this authorChristina M. Homer
Department of Biochemistry and Biophysics, UCSF, San Francisco, CA, USA
Search for more papers by this authorJun Yin
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
Search for more papers by this authorJames P. Noonan
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
Search for more papers by this authorHiten Madhani
Department of Biochemistry and Biophysics, UCSF, San Francisco, CA, USA
Search for more papers by this authorJohn R. Perfect
Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
Search for more papers by this authorCorresponding Author
Dennis J. Thiele
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA
Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA
For correspondence. E-mail [email protected]; Tel. 919-684-5776; Fax 919-668-6044.Search for more papers by this authorSummary
The ability of the human fungal pathogen Cryptococcus neoformans to adapt to variable copper (Cu) environments within the host is key for successful dissemination and colonization. During pulmonary infection, host alveolar macrophages compartmentalize Cu into the phagosome and C. neoformans Cu-detoxifying metallothioneins, MT1 and MT2, are required for survival of the pathogen. In contrast, during brain colonization the C. neoformans Cu+ importers Ctr1 and Ctr4 are required for virulence. Central for the regulation and expression of both the Cu detoxifying MT1/2 and the Cu acquisition Ctr1/4 proteins is the Cu-metalloregulatory transcription factor Cuf1, an established C. neoformans virulence factor. Due to the importance of the distinct C. neoformans Cu homeostasis mechanisms during host colonization and virulence, and to the central role of Cuf1 in regulating Cu homeostasis, we performed a combination of RNA-Seq and ChIP-Seq experiments to identify differentially transcribed genes between conditions of high and low Cu. We demonstrate that the transcriptional regulation exerted by Cuf1 is intrinsically complex and that Cuf1 also functions as a transcriptional repressor. The Cu- and Cuf1-dependent regulon in C. neoformans reveals new adaptive mechanisms for Cu homeostasis in this pathogenic fungus and identifies potential new pathogen-specific targets for therapeutic intervention in fungal infections.
Graphical Abstract
The essential yet toxic nature of Cu ions in living cells requires exquisite control of Cu homeostasis. The fungal pathogen C. neoformans regulates Cu homeostasis for survival during its complex host colonization process. During pulmonary infection host innate immune cells use Cu to kill C. neoformans, which responds by activating expression of Cu detoxifying proteins. However, during brain colonization, expression of the fungal Cu import machinery is activated and required for virulence. To achieve the genetic plasticity required for adaptation to a continuum of distinct Cu environments within the host, C. neoformans utilizes the Cu-responsive transcription factor, Cuf1. Cuf1 is unique as it senses and responds to both high and low Cu environments, activating different sets of genes dependent on environmental Cu status. Cells lacking Cuf1 are compromised for colonization of the lungs and brain, highlighting Cuf1 as an important virulence factor. A genome-wide assessment of Cuf1 binding sites and Cuf1-dependent transcription changes driven by Cu status identified novel genes required for adaptation to differential Cu environments. These genes and their regulation provide new insights into the adaptive responses to changes in host Cu availability and may reveal new targets for therapeutic intervention in cryptococcosis.
RNA-Seq and ChIP-Seq experiments identified the Cuf1-dependent Cryptococcus neoformans Cu regulon. Cuf1 regulation is intrinsically complex, Cuf1 functions as an activator, a repressor and potentially as a modulator of transcription in response to Cu availability. Cu- and Cuf1-dependent regulon in C. neoformans reveals new adaptive mechanisms for Cu homeostasis, and identifies potential pathogen-specific targets for therapeutic intervention.
Supporting Information
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| mmi13960-sup-0002-suppinfoTabS1.xlsx10 KB | Supporting Information Table S1 |
| mmi13960-sup-0003-suppinfoTabS2.xlsx11.7 KB | Supporting Information Table S2 |
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