Unique evolution of the UPR pathway with a novel bZIP transcription factor, HxL1, for controlling pathogenicity of cryptococcus neoformans

Seon Ah Cheon, Kwang Woo Jung, Ying Lien Chen, Joseph Heitman, Yong Sun Bahn, Hyun Ah Kang

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

In eukaryotic cells, the unfolded protein response (UPR) pathway plays a crucial role in cellular homeostasis of the endoplasmic reticulum (ER) during exposure to diverse environmental conditions that cause ER stress. Here we report that the human fungal pathogen Cryptococcus neoformans has evolved a unique UPR pathway composed of an evolutionarily conserved Ire1 protein kinase and a novel bZIP transcription factor encoded by HXL1 (HAC1 and XBP1-Like gene 1). C. neoformans HXL1 encodes a protein lacking sequence homology to any known fungal or mammalian Hac1/Xbp1 protein yet undergoes the UPR-induced unconventional splicing in an Ire1-dependent manner upon exposure to various stresses. The structural organization of HXL1 and its unconventional splicing is widely conserved in C. neoformans strains of divergent serotypes. Notably, both C. neoformans ire1 and hxl1 mutants exhibited extreme growth defects at 37°C and hypersensitivity to ER stress and cell wall destabilization. All of the growth defects of the ire1 mutant were suppressed by the spliced active form of Hxl1, supporting that HXL1 mRNA is a downstream target of Ire1. Interestingly, however, the ire1 and hxl1 mutants showed differences in thermosensitivity, expression patterns for a subset of genes, and capsule synthesis, indicating that Ire1 has both Hxl1-dependent and -independent functions in C. neoformans. Finally, Ire1 and Hxl1 were shown to be critical for virulence of C. neoformans, suggesting UPR signaling as a novel antifungal therapeutic target.

Original languageEnglish
Article numbere1002177
JournalPLoS Pathogens
Volume7
Issue number8
DOIs
Publication statusPublished - 2011 Aug 1

Fingerprint

Basic-Leucine Zipper Transcription Factors
Unfolded Protein Response
Cryptococcus neoformans
Virulence
Endoplasmic Reticulum Stress
Genes
Amino Acid Sequence Homology
Eukaryotic Cells
Growth
Endoplasmic Reticulum
Cell Wall
Protein Kinases
Capsules
Hypersensitivity
Homeostasis
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Cheon, Seon Ah ; Jung, Kwang Woo ; Chen, Ying Lien ; Heitman, Joseph ; Bahn, Yong Sun ; Kang, Hyun Ah. / Unique evolution of the UPR pathway with a novel bZIP transcription factor, HxL1, for controlling pathogenicity of cryptococcus neoformans. In: PLoS Pathogens. 2011 ; Vol. 7, No. 8.
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Unique evolution of the UPR pathway with a novel bZIP transcription factor, HxL1, for controlling pathogenicity of cryptococcus neoformans. / Cheon, Seon Ah; Jung, Kwang Woo; Chen, Ying Lien; Heitman, Joseph; Bahn, Yong Sun; Kang, Hyun Ah.

In: PLoS Pathogens, Vol. 7, No. 8, e1002177, 01.08.2011.

Research output: Contribution to journalArticle

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