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The protein phosphatase 2C domain contributes to the pathobiological function of adenylyl cyclase in Cryptococcus neoformans

ABSTRACT: Adenylyl cyclase (AC) is the central regulator of cAMP signalling in fungal pathogens, yet fungal ACs uniquely contain a protein phosphatase 2C (PP2C) domain whose function remains unclear. Here, we characterise the PP2C domain of the AC Cac1 in the human pathogen Cryptococcus neoformans. Structural and biochemical analyses show that Cac1-PP2C adopts a non-canonical scaffold but functions as a Ser/Thr-specific metalloenzyme. Deletion of the PP2C or AC catalytic (ACC) domain demonstrated that PP2C is required for full Cac1 activity, influencing melanin and capsule synthesis, sexual differentiation, titan cell formation, and cell wall integrity. Notably, the PP2C-null mutant induced Th2-biased immunity and extensive pulmonary damage yet failed to cause mortality in mice. Integrated transcriptomic and phosphoproteomic analyses further revealed shared and domain-specific signalling outputs mediated by PP2C and ACC. This study provides the first comprehensive characterisation of a fungal AC-linked PP2C domain and defines its pivotal role in C. neoformans pathobiology

ORGANISM(S): Cryptococcus neoformans

PROVIDER: GSE312692 | GEO | 2025/12/09

REPOSITORIES: GEO

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Casein kinase 2 complex: a central regulator of multiple pathobiological signaling pathways in Cryptococcus neoformans

Project description:Casein kinase 2 (CK2) is a potential therapeutic target for several human diseases due to its crucial roles in growth, differentiation, and metabolic homeostasis. This study delves into the role of the CK2 complex in Cryptococcus neoformans, a key fungal pathogen causing meningitis. In C. neoformans, the CK2 complex is made up of a main catalytic subunit (Cka1) and two regulatory subunits (Ckb1 and Ckb2). The primary role of Cka1 is as a protein kinase, while Ckb1/2 assist in various cellular functions. Triple mutants without all three subunits exhibited more pronounced defects than mutants lacking only Cka1, hinting at potential independent functions of Ckb1/2. In animal studies, mutants without these subunits showed a sharp decline in virulence. Moreover, CK2 disruption affected many effector proteins and disrupted key signaling pathways crucial for the pathogenicity of C. neoformans. Overall, the findings highlight the importance of the CK2 complex in fungal biology and its potential as a target for new antifungal treatments.

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Unravelling the pathobiological role of the fungal KEOPS complex in Cryptococcus neoformans

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Project description:We compared the expression profile of titan-like cells with cells of regular size in C. neoformans. This was investigated at different time points of the transition: 7 and 24 h

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Project description:We report on our study the role of C. neoformans transcription factor Pdr802, whose expression is highly induced under host-like conditions in vitro and is critical for C. neoformans dissemination and virulence in a mouse model of infection. We found that direct targets of Pdr802 include the calcineurin targets Had1 and Pmc1, which are important for C. neoformans virulence, the transcription factor Bzp4, which promotes cryptococcal melanization and capsule thickness, and 35 transmembrane transporters. Notably, a strain engineered to lack Pdr802 showed a dramatically increased population of Titan cells. Since Titan cells are not phagocyted and do not disseminate via the Trojan horse mechanism or via penetration of biological barriers, this likely explains the reduced dissemination of pdr802 cells to the central nervous system and consequently reduced pathogenicity of this strain. The role of Pdr802 as a negative regulator of titanisation is thus critical for cryptococcal virulence.

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Project description:We characterized the impact of the J domain co-chaperone, Dnj4, on the transcriptional response to DNA damage induced by hydroxyurea (an inhibitor of ribonucleotide reductase) in Cryptococcus neoformans. We treated wild type (WT) and mutant dnj4∆ log phase cells with hydroxyurea for one hour and found that the loss of DNJ4 impaired the transcriptional response to HU. In particular, the up-regulation of DNA damage and repair genes as well as iron uptake genes was impaired in these mutants. This study provides the first dataset on the transcriptional response to hydroxyurea in C. neoformans as a resource to the fungal pathogen community.

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