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The Role of Core Virulence Kinase Bud32 in Iron Homeostasis Regulation in Cryptococcus neoformans

ABSTRACT: The core virulence kinase Bud32, which is critical for lung and brain infections, influences the production of major virulence factors in Cryptococcus neoformans, including capsule formation, melanin production, and growth at 37°C. This study explores the role of Bud32 in regulation of iron homeostasis in C. neoformans. Bud32 was required for growth under iron limiting condition. Loss of Bud32 resulted in significant alterations in the expression of proteins related to iron binding and iron-sulfur cluster assembly. Moreover, metabolic profiling identified 696 metabolites that were up-regulated and 480 that were down-regulated in the bud32 deletion mutant, highlighting the significant impact of Bud32 loss on intracellular metabolite levels. In particular, the levels of biliverdin, which is primarily derived from heme, showed a significant decrease in the absence of Bud32. Furthermore, Bud32 has been demonstrated to modulate iron-sulfur cluster assembly, likely influencing the interaction between the iron-sulfur binding protein Grx4 and the iron regulatory factors Cir1 and HapX. Phosphorylation analysis revealed that the deletion of Bud32 caused widespread changes in the phosphorylation status of various proteins, including the iron regulatory factors Cir1 and Rim101. These findings indicate that the Bud32 kinase plays a vital role in regulating iron homeostasis in C. neoformans.

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ORGANISM(S): Cryptococcus Neoformans Var. Grubii Serotype A (strain H99 / Atcc 208821 / Cbs 10515 / Fgsc 9487) (filobasidiella Neoformans Var. Grubii)

TISSUE(S): Cell Culture

SUBMITTER: Peng Xue

LAB HEAD: Peng Xue

PROVIDER: PXD056847 | Pride | 2025-07-23

REPOSITORIES: Pride

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Project description:Minerals are essential for proper cell function. In infectious processes where both cells of the causative agent and the host itself are involved, competition for their acquisition is necessary. In this context, pathogenic fungi have developed machinery to ensure the acquisition of minerals and at the same time have perfected strategies that protect them from intoxication by excess of them. In eukaryotic cells, minerals are involved both in the respiratory chain and in cellular metabolisms, which in microorganisms are related to the expression of virulence factors, while in the host, they are related to the activation and regulation of the immune system In the activation of phagocytic cells, in addition, the host can regulate the availability of minerals, which has been called nutritional immunity. Cryptococcosis is an opportunistic mycosis, acquired by inhaling fungal propagules present in the environment; it is a potentially fatal infection that affects the lungs and the central nervous system, both in immunosuppressed and immunocompetent people. The infection is caused by two species, namely: Cryptococcus neoformans (var. grubii (serotype A), var. neoformans (serotype D) and a hybrid corresponding to serotype AD) and Cryptococcus gattii (serotypes B and C). These species present phenotypic, genotypic and epidemiological differences, as well as in their geographical distribution. In recent years, mechanisms for the acquisition of iron and copper, among other micronutrients, have been described in C. neoformans, as well as their relationship, both with the expression of genes associated with virulence factors, the interaction with different intracellular signaling pathways. , especially in routes involved in adaptation to environmental changes and stress conditions. The regulation of the acquisition of these minerals is mediated by several signaling pathways, as the Rim 101 pathway in C. neoformans is essential in adapting to the change in pH and is particular to fungal cells. Iron and copper have been related to the induction of virulence through the production of melanin, capsules and the formation of titan cells, as well as enzymes related to oxidation-reduction phenomena and other virulence factors, which can be regulated by the factor of RIM101 transcription, this pathway induces the expression of genes that encode an iron transporter and a permease (SIT1 and CFT1, respectively) and a copper transporter (CTR4). This enables the yeast to survive in the host because it can rapidly transition from a slightly acidic environment in the phagolysosome to a slightly alkaline environment such as cerebrospinal fluid and serum. For mycoses in general, alternative therapies have been proposed, where the regulation of the acquisition of minerals in the tissue environment during the establishment of the mycosis could be a mechanism to control the growth of the fungus. Therefore, the compression of the signaling networks will allow exploring new alternatives for the development of novel antifungal drugs as well as biological biomarkers, both for the diagnosis and for possible combined therapies at the nutritional immunology level that help prevent and anticipate management. Taking these antecedents into account, we consider it important to evaluate the effect of iron and copper in Colombian clinical isolates of C. neoformans for the prediction of new antifungal targets.

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The Role of Core Virulence Kinase Bud32 in Iron Homeostasis Regulation in Cryptococcus neoformans

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