Sre1p, a regulator of oxygen sensing and sterol homeostasis, is required for virulence in Cryptococcus neoformans

Yun C. Chang, Clara M. Bien, Hyeseung Lee, Peter J. Espenshade, Kyung J. Kwon-Chung

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

Cryptococcus neoformans is an environmental pathogen requiring atmospheric levels of oxygen for optimal growth. Upon inhalation, C. neoformans disseminates to the brain and causes meningoencephalitis, but the mechanisms by which the pathogen adapts to the low-oxygen environment in the brain have not been investigated. We found that SRE1, a homologue of the mammalian sterol regulatory element-binding protein (SREBP), functions in an oxygen-sensing pathway. Low oxygen decreased sterol synthesis in C. neoformans and triggered activation of membrane-bound Sre1p by the cleavage-activating protein, Scp1p. Microarray and Northern blot analysis demonstrated that under low oxygen, Sre1p activates genes required for ergosterol biosynthesis and iron uptake. Consistent with these regulatory functions, sre1Δ cells were hypersensitive to azole drugs and failed to grow under iron-limiting conditions. Importantly, sre1Δ cells failed to produce fulminating brain infection in mice. Our in vitro data support a model in which Sre1p is activated under low oxygen leading to the upregulation of genes required for sterol biosynthesis and growth in a nutrient-limiting environment. Animal studies confirm the importance of SRE1 for C. neoformans to adapt to the host environment and to cause fatal meningoencephalitis, thereby identifying the SREBP pathway as a therapeutic target for cryptococcosis.

Original languageEnglish (US)
Pages (from-to)614-629
Number of pages16
JournalMolecular Microbiology
Volume64
Issue number3
DOIs
StatePublished - May 1 2007

Fingerprint

Cryptococcus neoformans
Sterols
Virulence
Homeostasis
Oxygen
Sterol Regulatory Element Binding Proteins
Meningoencephalitis
Brain
Iron
Ergosterol
Cryptococcosis
Azoles
Growth
Northern Blotting
Inhalation
Genes
Up-Regulation
Food
Membranes
Infection

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

Cite this

Chang, Yun C. ; Bien, Clara M. ; Lee, Hyeseung ; Espenshade, Peter J. ; Kwon-Chung, Kyung J. / Sre1p, a regulator of oxygen sensing and sterol homeostasis, is required for virulence in Cryptococcus neoformans. In: Molecular Microbiology. 2007 ; Vol. 64, No. 3. pp. 614-629.
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Sre1p, a regulator of oxygen sensing and sterol homeostasis, is required for virulence in Cryptococcus neoformans. / Chang, Yun C.; Bien, Clara M.; Lee, Hyeseung; Espenshade, Peter J.; Kwon-Chung, Kyung J.

In: Molecular Microbiology, Vol. 64, No. 3, 01.05.2007, p. 614-629.

Research output: Contribution to journalArticle

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