Unraveling the design principle for motif organization in signaling networks.
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ABSTRACT:
SUBMITTER: Chatterjee S
PROVIDER: S-EPMC3228783 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Melanin is an antioxidant polyphenol pigment required for the pathogenicity of many fungal pathogens, but comprehensive regulatory mechanisms remain unidentified. In this study, we systematically analyzed melanin-regulating signaling pathways in Cryptococcus neoformans and identified four melanin-regulating core transcription factors (TFs), Bzp4, Usv101, Mbs1, and Hob1, required for induction of the laccase gene (LAC1). Bzp4, Usv101, and Mbs1 independently regulate LAC1 induction, whereas Hob1 controls Bzp4 and Usv101 expression. Both Bzp4 and Usv101 are localized in the cytoplasm under nutrient-rich conditions (i.e., in the presence of yeast extract-peptone-dextrose [YPD] medium) but translocate into the nucleus upon nutrient starvation (i.e., in the presence of yeast nitrogen base [YNB] medium without glucose), and Mbs1 is constitutively localized in the nucleus. Notably, the cAMP pathway is not involved in regulation of the four TFs, but the high-osmolarity glycerol response (HOG) pathway negatively regulates induction of BZP4 and LAC1 Next, we searched for potential kinases upstream of the core TFs and identified nine core kinases; their deletion led to defective melanin production and LAC1 induction. Deletion of GSK3 or KIC1 abolished induction of LAC1 and BZP4 and perturbed nuclear translocation of Bzp4. Notably, Gsk3 also regulated expression of HOB1, USV101, and MBS1, indicating that it is a critical melanin-regulating kinase. Finally, an RNA sequencing-based transcriptome analysis of the wild-type strain and of bzp4?, usv101?, hob1?, and mbs1? strains under nutrient-rich and nutrient-starved conditions revealed that the melanin-regulating core TFs govern redundant and distinct classes of genes involved in a variety of biological processes.IMPORTANCE Melanins are dark green, brown, or black pigments that serve as antioxidant, reactive oxygen species (ROS) scavengers that protect fungal pathogens from radiation and host immune responses. Cryptococcus neoformans, the major etiological agent of fungal meningoencephalitis, also utilizes melanin as a key virulence factor. In this basidiomycete pathogen, melanin production is regulated by the cAMP and high-osmolarity glycerol response (HOG) pathways, and yet its complex signaling networks remain poorly described. In this study, we uncovered novel melanin synthesis regulatory networks consisting of core transcription factors (TFs), including Bzp4, Usv101, Hob1, and Mbs1, and core kinases Gsk3 and Kic1. These networks were identified through coupling systematic analyses of the expression and epistatic relationships of TF and kinase mutant libraries in the presence of diverse melanin substrates with transcriptome profiling of the core TF mutants. Thus, this report provides comprehensive insight into the melanin-regulating pathways in C. neoformans and other fungal pathogens.
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Project description:The polysaccharide capsule of Cryptococcus neoformans-an opportunistic basidiomycete pathogen and the major etiological agent of fungal meningoencephalitis-is a key virulence factor that prevents its phagocytosis by host innate immune cells. However, the complex signaling networks for their synthesis and attachment remain elusive. In this study, we systematically analyzed capsule biosynthesis and signaling networks using C. neoformans transcription factor (TF) and kinase mutant libraries under diverse capsule-inducing conditions. We found that deletion of GAT201, YAP1, BZP4, and ADA2 consistently caused capsule production defects in all tested media, indicating that they are capsule-regulating core TFs. Epistatic and expression analyses showed that Yap1 and Ada2 control Gat201 upstream, whereas Bzp4 and Gat201 independently regulate capsule production. Next, we searched for potential upstream kinases and found that mutants lacking PKA1, BUD32, POS5, IRE1, or CDC2801 showed reduced capsule production under all three capsule induction conditions, whereas mutants lacking HOG1 and IRK5 displayed enhanced capsule production. Pka1 and Irk5 controlled the induction of GAT201 and BZP4, respectively, under capsule induction conditions. Finally, we monitored the transcriptome profiles governed by Bzp4, Gat201, and Ada2 under capsule-inducing conditions and demonstrated that these TFs regulate redundant and unique sets of downstream target genes. Bzp4, Ada2, and Gat201 govern capsule formation in C. neoformans by regulating the expression of various capsule biosynthesis genes and chitin/chitosan synthesis genes in a positive and negative manner, respectively. In conclusion, this study provides further insights into the complex regulatory mechanisms of capsule production-related signaling pathways in C. neoformans. IMPORTANCE Over the past decades, human fungal pathogens, including C. neoformans, have emerged as a major public threat since the AIDS pandemic, only to gain more traction in connection to COVID-19. Polysaccharide capsules are rare fungal virulence factors that are critical for protecting C. neoformans from phagocytosis by macrophages. To date, more than 75 proteins involved in capsule synthesis and cell wall attachment have been reported in C. neoformans; however, their complex upstream signaling networks remain elusive. In this study, we demonstrated that Ada2, Yap1, Bzp4, and Gat201 were key capsule-inducing transcriptional regulators. Yap1 and Ada2 function upstream of Gat201, whereas Bzp4 and Gat201 function independently. Genome-wide transcriptome profiling revealed that Bzp4, Gat201, and Ada2 promote capsule production and attachment by positively and negatively regulating genes involved in capsule synthesis and chitin/chitosan synthesis, respectively. Thus, this study provides comprehensive insights into the complex capsule-regulating signaling pathway in C. neoformans.
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Project description:Cryptococcus neoformans is an opportunistic basidiomycete pathogen that is a major etiological agent of fungal meningoencephalitis leading to more than 180,000 deaths worldwide annually. For this pathogen, the polysaccharide capsule is a key virulence factor, which interferes with the phagocytosis by host innate immune cells, but its complex signaling networks remain elusive. In this study, we systematically analyzed capsule biosynthesis and signaling networks by using C. neoformans transcription factor (TF) and kinase mutant libraries under diverse capsule-inducing conditions, such as Dulbecco’s Modified Eagle’s (DME), Littman’s medium (LIT) and fetal bovine serum (FBS) medium. We found that deletion of GAT201, YAP1, BZP4, and ADA2 consistently causes capsule production defects in all tested media, indicating that they are capsule-regulating core TFs. Epistatic and expression analysis showed that Yap1 and Ada2 control Gat201 upstream, whereas Bzp4 and Gat201 regulate capsule production independently. We next searched for potential upstream kinases and found that mutants deleted of PKA1, BUD32, POS5, IRE1 or CDC2801 showed reduced capsule production under all three capsule induction conditions, whereas mutants deleted of HOG1 and IRK5 displayed enhanced capsule production. Notably, Pka1 and Irk5 controls induction of GAT201 and BZP4, respectively, under capsule induction condition. Finally, we monitored transcriptome profiles governed by Bzp4, Gat201, and Ada2 under capsule-inducing condition and demonstrated that these TFs regulate redundant and unique sets of downstream target genes. In conclusion, this study provides further insight into the complex regulatory mechanism of capsule production related signaling pathways in C. neoformans.
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