Recognition of galactose by a scaffold protein recruits a transcriptional activator for the GAL regulon induction in Candida albicans

  1. Xun Sun
  2. Jing Yu
  3. Cheng Zhu
  4. Xinreng Mo
  5. Qiangqiang Sun
  6. Dandan Yang
  7. Chang Su  Is a corresponding author
  8. Yang Lu  Is a corresponding author
  1. Wuhan University, China
  2. Tianjin University, China

Abstract

The GAL pathway of yeasts has long served as a model system for understanding of how regulatory mode of eukaryotic metabolic pathways evolves. While Gal4 mode has been well-characterized in Saccharomycetaceae clade, little is known about the regulation of the GAL pathway in other yeasts. Here, we find that Rep1, a Ndt80-like family transcription factor, serves as a galactose sensor in the commensal-pathogenic fungus Candida albicans. It is presented at the GAL gene promoters independent of the presence of galactose. Rep1 recognizes galactose via a direct physical interaction. The net result of this interaction is the recruitment of a transcriptional activator Cga1 (Candida galactose gene activator, orf19.4959) and transcription of the GAL genes proceeds. Rep1 and Cga1 are conserved across the CTG species. Rep1 itself does not possess transcriptional activity. Instead, it provides a scaffold to recruit different factors for transcriptional regulation. Rep1-Cga1 mode of regulation represents a new example of network rewiring in fungi, which provides insight into how C. albicans evolves transcriptional programs to colonize diverse host niches.

Data availability

The mass spectrometry proteomics data are deposited to the ProteomeXchange Consortium with the dataset identifier PXD037522. The ChIP-Seq data are deposited to Dryad https://doi.org/10.5061/dryad.tqjq2bw35. Source Data files have been provided in Figure 1-Source data, Figure 1-figure supplement 2-Source data, Figure 1-figure supplement 3-Source data, Figure 2-Source Data 1&2, Figure 2-figure supplement 4-Source data, Figure 3-Source Data 1&2, Figure 3-figure supplement 5-Source data 1&2, Figure 4-Source Data 1&2, and Figure 4-figure supplement 6-Source data.

The following data sets were generated

Article and author information

Author details

  1. Xun Sun

    TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Jing Yu

    Hubei Key Laboratory of Cell Homeostasis,, Wuhan University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Cheng Zhu

    Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Tianjin University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0260-6287
  4. Xinreng Mo

    Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Qiangqiang Sun

    Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Dandan Yang

    TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Chang Su

    Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan, China
    For correspondence
    changsu@whu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  8. Yang Lu

    TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China
    For correspondence
    ylu7@whu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3784-7577

Funding

National Natural Science Foundation of China (32070074)

  • Yang Lu

National Natural Science Foundation of China (32170089)

  • Chang Su

National Natural Science Foundation of China (81973370)

  • Chang Su

Natural Science Foundation of Hubei Province (2022CFB103)

  • Chang Su

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2023, Sun et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 802
    views
  • 163
    downloads
  • 4
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Xun Sun
  2. Jing Yu
  3. Cheng Zhu
  4. Xinreng Mo
  5. Qiangqiang Sun
  6. Dandan Yang
  7. Chang Su
  8. Yang Lu
(2023)
Recognition of galactose by a scaffold protein recruits a transcriptional activator for the GAL regulon induction in Candida albicans
eLife 12:e84155.
https://doi.org/10.7554/eLife.84155

Share this article

https://doi.org/10.7554/eLife.84155

Further reading

    1. Genetics and Genomics
    Angela M Tuckowski, Safa Beydoun ... Scott F Leiser
    Research Article

    Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that C. elegans fmo-2 promotes longevity, stress resistance, and healthspan by rewiring endogenous metabolism. However, there are five C. elegans FMOs and five mammalian FMOs, and it is not known whether promoting longevity and health benefits is a conserved role of this gene family. Here, we report that expression of C. elegans fmo-4 promotes lifespan extension and paraquat stress resistance downstream of both dietary restriction and inhibition of mTOR. We find that overexpression of fmo-4 in just the hypodermis is sufficient for these benefits, and that this expression significantly modifies the transcriptome. By analyzing changes in gene expression, we find that genes related to calcium signaling are significantly altered downstream of fmo-4 expression. Highlighting the importance of calcium homeostasis in this pathway, fmo-4 overexpressing animals are sensitive to thapsigargin, an ER stressor that inhibits calcium flux from the cytosol to the ER lumen. This calcium/fmo-4 interaction is solidified by data showing that modulating intracellular calcium with either small molecules or genetics can change expression of fmo-4 and/or interact with fmo-4 to affect lifespan and stress resistance. Further analysis supports a pathway where fmo-4 modulates calcium homeostasis downstream of activating transcription factor-6 (atf-6), whose knockdown induces and requires fmo-4 expression. Together, our data identify fmo-4 as a longevity-promoting gene whose actions interact with known longevity pathways and calcium homeostasis.

    1. Genetics and Genomics
    Junhong Choi, Wei Chen ... Jay Shendure
    Research Article

    One of the goals of synthetic biology is to enable the design of arbitrary molecular circuits with programmable inputs and outputs. Such circuits bridge the properties of electronic and natural circuits, processing information in a predictable manner within living cells. Genome editing is a potentially powerful component of synthetic molecular circuits, whether for modulating the expression of a target gene or for stably recording information to genomic DNA. However, programming molecular events such as protein-protein interactions or induced proximity as triggers for genome editing remains challenging. Here, we demonstrate a strategy termed ‘P3 editing’, which links protein-protein proximity to the formation of a functional CRISPR-Cas9 dual-component guide RNA. By engineering the crRNA:tracrRNA interaction, we demonstrate that various known protein-protein interactions, as well as the chemically induced dimerization of protein domains, can be used to activate prime editing or base editing in human cells. Additionally, we explore how P3 editing can incorporate outputs from ADAR-based RNA sensors, potentially allowing specific RNAs to induce specific genome edits within a larger circuit. Our strategy enhances the controllability of CRISPR-based genome editing, facilitating its use in synthetic molecular circuits deployed in living cells.