The C-terminal protein interaction domain of the chromatin reader Yaf9 is critical for pathogenesis of Candida albicans
ABSTRACTFungal infections cause a large health burden but are treated by only a handful of antifungal drug classes. Chromatin factors have emerged as possible targets for new antifungals. These targets include the reader proteins, which interact with posttranslationally modified histones to influenc...
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2024-03-01
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| Series: | mSphere |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/msphere.00696-23 |
| _version_ | 1827292858714947584 |
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| author | Tricia L. Lo Qi Wang Joshua Nickson Bryce J. W. van Denderen Deanna Deveson Lucas Her Xiang Chai Gavin J. Knott Harshini Weerasinghe Ana Traven |
| author_facet | Tricia L. Lo Qi Wang Joshua Nickson Bryce J. W. van Denderen Deanna Deveson Lucas Her Xiang Chai Gavin J. Knott Harshini Weerasinghe Ana Traven |
| author_sort | Tricia L. Lo |
| collection | DOAJ |
| description | ABSTRACTFungal infections cause a large health burden but are treated by only a handful of antifungal drug classes. Chromatin factors have emerged as possible targets for new antifungals. These targets include the reader proteins, which interact with posttranslationally modified histones to influence DNA transcription and repair. The YEATS domain is one such reader recognizing both crotonylated and acetylated histones. Here, we performed a detailed structure/function analysis of the Candida albicans YEATS domain reader Yaf9, a subunit of the NuA4 histone acetyltransferase and the SWR1 chromatin remodeling complex. We have previously demonstrated that the homozygous deletion mutant yaf9Δ/Δ displays growth defects and is avirulent in mice. Here we show that a YEATS domain mutant expected to inactivate Yaf9’s chromatin binding does not display strong phenotypes in vitro, nor during infection of immune cells or in a mouse systemic infection model, with only a minor virulence reduction in vivo. In contrast to the YEATS domain mutation, deletion of the C-terminal domain of Yaf9, a protein–protein interaction module necessary for its interactions with SWR1 and NuA4, phenocopies the null mutant. This shows that the C-terminal domain is essential for Yaf9 roles in vitro and in vivo, including C. albicans virulence. Our study informs on the strategies for therapeutic targeting of Yaf9, showing that approaches taken for the mammalian YEATS domains by disrupting their chromatin binding might not be effective in C. albicans, and provides a foundation for studying YEATS proteins in human fungal pathogens.IMPORTANCEThe scarcity of available antifungal drugs and rising resistance demand the development of therapies with new modes of action. In this context, chromatin regulation may be a target for novel antifungal therapeutics. To realize this potential, we must better understand the roles of chromatin regulators in fungal pathogens. Toward this goal, here, we studied the YEATS domain chromatin reader Yaf9 in Candida albicans. Yaf9 uses the YEATS domain for chromatin binding and a C-terminal domain to interact with chromatin remodeling complexes. By constructing mutants in these domains and characterizing their phenotypes, our data indicate that the Yaf9 YEATS domain might not be a suitable therapeutic drug target. Instead, the Yaf9 C-terminal domain is critical for C. albicans virulence. Collectively, our study informs how a class of chromatin regulators performs their cellular and pathogenesis roles in C. albicans and reveals strategies to inhibit them. |
| first_indexed | 2024-04-24T13:14:07Z |
| format | Article |
| id | doaj.art-945ca35914bb41c18f1153b08f7b2e7d |
| institution | Directory Open Access Journal |
| issn | 2379-5042 |
| language | English |
| last_indexed | 2024-04-24T13:14:07Z |
| publishDate | 2024-03-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSphere |
| spelling | doaj.art-945ca35914bb41c18f1153b08f7b2e7d2024-04-05T01:32:09ZengAmerican Society for MicrobiologymSphere2379-50422024-03-019310.1128/msphere.00696-23The C-terminal protein interaction domain of the chromatin reader Yaf9 is critical for pathogenesis of Candida albicansTricia L. Lo0Qi Wang1Joshua Nickson2Bryce J. W. van Denderen3Deanna Deveson Lucas4Her Xiang Chai5Gavin J. Knott6Harshini Weerasinghe7Ana Traven8Department of Biochemistry and Molecular Biology and the Infection Program, Biomedicine Discovery Institute, Monash University, Clayton, AustraliaDepartment of Biochemistry and Molecular Biology and the Infection Program, Biomedicine Discovery Institute, Monash University, Clayton, AustraliaCentre to Impact AMR, Monash University, Clayton, AustraliaDepartment of Biochemistry and Molecular Biology and the Infection Program, Biomedicine Discovery Institute, Monash University, Clayton, AustraliaGenomics and Bioinformatics Platform, Monash University, Clayton, AustraliaDepartment of Biochemistry and Molecular Biology and the Infection Program, Biomedicine Discovery Institute, Monash University, Clayton, AustraliaDepartment of Biochemistry and Molecular Biology and the Infection Program, Biomedicine Discovery Institute, Monash University, Clayton, AustraliaDepartment of Biochemistry and Molecular Biology and the Infection Program, Biomedicine Discovery Institute, Monash University, Clayton, AustraliaDepartment of Biochemistry and Molecular Biology and the Infection Program, Biomedicine Discovery Institute, Monash University, Clayton, AustraliaABSTRACTFungal infections cause a large health burden but are treated by only a handful of antifungal drug classes. Chromatin factors have emerged as possible targets for new antifungals. These targets include the reader proteins, which interact with posttranslationally modified histones to influence DNA transcription and repair. The YEATS domain is one such reader recognizing both crotonylated and acetylated histones. Here, we performed a detailed structure/function analysis of the Candida albicans YEATS domain reader Yaf9, a subunit of the NuA4 histone acetyltransferase and the SWR1 chromatin remodeling complex. We have previously demonstrated that the homozygous deletion mutant yaf9Δ/Δ displays growth defects and is avirulent in mice. Here we show that a YEATS domain mutant expected to inactivate Yaf9’s chromatin binding does not display strong phenotypes in vitro, nor during infection of immune cells or in a mouse systemic infection model, with only a minor virulence reduction in vivo. In contrast to the YEATS domain mutation, deletion of the C-terminal domain of Yaf9, a protein–protein interaction module necessary for its interactions with SWR1 and NuA4, phenocopies the null mutant. This shows that the C-terminal domain is essential for Yaf9 roles in vitro and in vivo, including C. albicans virulence. Our study informs on the strategies for therapeutic targeting of Yaf9, showing that approaches taken for the mammalian YEATS domains by disrupting their chromatin binding might not be effective in C. albicans, and provides a foundation for studying YEATS proteins in human fungal pathogens.IMPORTANCEThe scarcity of available antifungal drugs and rising resistance demand the development of therapies with new modes of action. In this context, chromatin regulation may be a target for novel antifungal therapeutics. To realize this potential, we must better understand the roles of chromatin regulators in fungal pathogens. Toward this goal, here, we studied the YEATS domain chromatin reader Yaf9 in Candida albicans. Yaf9 uses the YEATS domain for chromatin binding and a C-terminal domain to interact with chromatin remodeling complexes. By constructing mutants in these domains and characterizing their phenotypes, our data indicate that the Yaf9 YEATS domain might not be a suitable therapeutic drug target. Instead, the Yaf9 C-terminal domain is critical for C. albicans virulence. Collectively, our study informs how a class of chromatin regulators performs their cellular and pathogenesis roles in C. albicans and reveals strategies to inhibit them.https://journals.asm.org/doi/10.1128/msphere.00696-23Candida albicanschromatinYaf9YEATS domainchromatin reader |
| spellingShingle | Tricia L. Lo Qi Wang Joshua Nickson Bryce J. W. van Denderen Deanna Deveson Lucas Her Xiang Chai Gavin J. Knott Harshini Weerasinghe Ana Traven The C-terminal protein interaction domain of the chromatin reader Yaf9 is critical for pathogenesis of Candida albicans mSphere Candida albicans chromatin Yaf9 YEATS domain chromatin reader |
| title | The C-terminal protein interaction domain of the chromatin reader Yaf9 is critical for pathogenesis of Candida albicans |
| title_full | The C-terminal protein interaction domain of the chromatin reader Yaf9 is critical for pathogenesis of Candida albicans |
| title_fullStr | The C-terminal protein interaction domain of the chromatin reader Yaf9 is critical for pathogenesis of Candida albicans |
| title_full_unstemmed | The C-terminal protein interaction domain of the chromatin reader Yaf9 is critical for pathogenesis of Candida albicans |
| title_short | The C-terminal protein interaction domain of the chromatin reader Yaf9 is critical for pathogenesis of Candida albicans |
| title_sort | c terminal protein interaction domain of the chromatin reader yaf9 is critical for pathogenesis of candida albicans |
| topic | Candida albicans chromatin Yaf9 YEATS domain chromatin reader |
| url | https://journals.asm.org/doi/10.1128/msphere.00696-23 |
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