A J Domain Protein Functions as a Histone Chaperone to Maintain Genome Integrity and the Response to DNA Damage in a Human Fungal Pathogen

Horianopoulos, Linda C.; Lee, Christopher W J; Schmitt, Kerstin; Valerius, Oliver; Hu, Guanggan; Caza, Mélissa; Braus, Gerhard H.; Kronstad, James W.

doi:10.1128/mbio.03273-21

“…The R packages GSEABase (71) and GOstats (72) were used to analyze all enrichments, and the R package ggplot2 (73) was used to visualize the outcomes of enrichment tests. Gene expression in the samples for RNA-Seq was verified by qRT-PCR following published procedures (74). The primers for qPCR validation are listed in Table S4.…”

Section: Mm)mentioning

confidence: 99%

The interplay between electron transport chain function and iron regulatory factors influences melanin formation inCryptococcus neoformans

Xue,

Sánchez-León,

Hu

et al. 2024

Preprint

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Mitochondrial functions are critical for the ability of the fungal pathogenCryptococcus neoformansto cause disease. However, mechanistic connections between key functions such as the mitochondrial electron transport chain (ETC) and virulence factor elaboration have yet to be thoroughly characterized. Here, we observed that inhibition of ETC complex III suppressed melanin formation, a major virulence factor. This inhibition was partially blocked upon loss of Cir1 or HapX, two transcription factors that regulate iron acquisition and use. In this regard, loss of Cir1 derepresses the expression of laccase genes as a potential mechanism to restore melanin, while HapX may condition melanin formation by controlling oxidative stress. We hypothesize that ETC dysfunction alters redox homeostasis to influence melanin formation. Consistent with this idea, inhibition of growth by hydrogen peroxide was exacerbated in the presence of the melanin substrate L-DOPA. Additionally, loss of the mitochondrial chaperone Mrj1, which influences the activity of ETC complex III and reduces ROS accumulation, also partially blocked antimycin A inhibition of melanin. The phenotypic impact of mitochondrial dysfunction was consistent with RNA-Seq analyses of WT cells treated with antimycin A or L-DOPA, or cells lacking Cir1 that revealed influences on transcripts encoding mitochondrial functions (e.g., ETC components and proteins for Fe-S cluster assembly). Overall, these findings reveal mitochondria-nuclear communication via ROS and iron regulators to control virulence factor production inC. neoformans.

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“…Chromatin remodeling protein has been reported to facilitate the DNA damage repair in response to plant ROS stress and maintain virulence in Candida glabrata(Rai et al, 2012), and Verticillium dahlia(Wang et al, 2020). Rather recently, HIR (histone chaperone complex) has been reported to modulate virulence of the human fungal pathogen like Cryptococcus neoformans(Horianopoulos et al, 2021), and Candida albicans(Jenull et al, 2021). The DEAH-box protein family encompasses a large number of RNA helicases that are involved in RNA metabolism and a variety of physiological functions in different species.…”

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Draft proteome of Colletotrichum falcatum revealed differential abundance of fungal pathogenicity-related proteins during red rot disease in sugarcane

Gujjar

¹

,

Joshi

²

,

Srivast

³

et al. 2023

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A highly virulent Colletotrichum falcatum pathotype (CF08) was cultured in nutrient deficit media with fine-cut sugarcane stalks of red rot susceptible variety (CoJ 64). The mycelium was collected for the analysis of whole proteome using LCMS/MS. In-silico analysis was performed to identify the exclusive and differentially abundant proteins from whole proteomes of C. falcatum samples cultured with sugarcane (CFS1 and CFS2). Whole proteome analysis revealed a relatively higher number of peptide identities/proteins in CFS2 (2233), followed by CFS1 (1911), and CFC (control) with least number of proteins (1808). Compared to control, CFS1 and CFS2 samples of C. falcatum had plenty of exclusively abundant proteins like ABC transporters, glucose transporter, actin cytoskeleton-regulatory complex proteins, antimicrobial peptides, autophagy-related proteins, chitin synthase, dicer-like proteins, histone-lysine N-methyltransferase proteins, myosin-1 proteins, polyketide synthase proteins, and nonribosomal peptide synthase proteins which are involved in the process of fungal virulence/pathogenicity. In this manuscript, we report the first draft of C. falcatum proteome (whole proteome) which has been successfully submitted to ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD033368.

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The interplay between electron transport chain function and iron regulatory factors influences melanin formation in Cryptococcus neoformans

Xue,

Sánchez-León,

Hu

et al. 2024

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Mitochondrial functions are critical for the ability of the fungal pathogen Cryptococcus neoformans to cause disease. However, mechanistic connections between key functions such as the mitochondrial electron transport chain (ETC) and virulence factor elaboration have yet to be thoroughly characterized. Here, we observed that inhibition of ETC complex III suppressed melanin formation, a major virulence factor. This inhibition was partially overcome by defects in Cir1 or HapX, two transcription factors that regulate iron acquisition and use. In this regard, loss of Cir1 derepresses the expression of laccase genes as a potential mechanism to restore melanin, while HapX may condition melanin formation by controlling oxidative stress. We hypothesize that ETC dysfunction alters redox homeostasis to influence melanin formation. Consistent with this idea, inhibition of growth by hydrogen peroxide was exacerbated in the presence of the melanin substrate L-DOPA. In addition, loss of the mitochondrial chaperone Mrj1, which influences the activity of ETC complex III and reduces ROS accumulation, also partially overcame antimycin A inhibition of melanin. The phenotypic impact of mitochondrial dysfunction was consistent with RNA-Seq analyses of WT cells treated with antimycin A or L-DOPA, or cells lacking Cir1 that revealed influences on transcripts encoding mitochondrial functions (e.g., ETC components and proteins for Fe-S cluster assembly). Overall, these findings reveal mitochondria-nuclear communication via ROS and iron regulators to control virulence factor production in C. neoformans . IMPORTANCE There is a growing appreciation of the importance of mitochondrial functions and iron homeostasis in the ability of fungal pathogens to sense the vertebrate host environment and cause disease. Many mitochondrial functions such as heme and iron-sulfur cluster biosynthesis, and the electron transport chain (ETC), are dependent on iron. Connections between factors that regulate iron homeostasis and mitochondrial activities are known in model yeasts and are emerging for fungal pathogens. In this study, we identified connections between iron regulatory transcription factors (e.g., Cir1 and HapX) and the activity of complex III of the ETC that influence the formation of melanin, a key virulence factor in the pathogenic fungus Cryptococcus neoformans . This fungus causes meningoencephalitis in immunocompromised people and is a major threat to the HIV/AIDS population. Thus, understanding how mitochondrial functions influence virulence may support new therapeutic approaches to combat diseases caused by C. neoformans and other fungi.

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A J Domain Protein Functions as a Histone Chaperone to Maintain Genome Integrity and the Response to DNA Damage in a Human Fungal Pathogen

Abstract: DNA replication, gene expression, and genomic repair all require precise coordination of the many proteins that interact with DNA. This includes the histones as well as their chaperones.

Cited by 4 publications

References 68 publications

The interplay between electron transport chain function and iron regulatory factors influences melanin formation inCryptococcus neoformans

The interplay between electron transport chain function and iron regulatory factors influences melanin formation inCryptococcus neoformans

Draft proteome of Colletotrichum falcatum revealed differential abundance of fungal pathogenicity-related proteins during red rot disease in sugarcane

The interplay between electron transport chain function and iron regulatory factors influences melanin formation in Cryptococcus neoformans

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