Calcineurin

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Introduction of Calcineurin

Calcineurin (CaN) is a member of the silk/threonine protein phosphatase family (also known as protein phosphatase 2B, PP2B) and is the only Ca²⁺ / calmodulin (CaM) regulated silk/threonine protein phosphatase found to date. It is currently believed that CaN is a multi-functional signal enzyme that is widely distributed and involved in the regulation of various cellular functions, and plays a regulatory role in cytokine-mediated T cell activation. CaN is a dimer consisting of a catalytic subunit calcineurin A (CnA) with a relative molecular mass of 59000 and a regulatory subunit calcineurin B (CnB) with a relative molecular mass of 19000. When Ca²⁺ / CaM specifically binds to the C-terminus of calcineurin, the active center of calcineurin is released and becomes active.

Fig.1 3D Crystallographic structure of calcineurin heterodimer composed of the catalytic (PPP3CA) and regulatory (PPP3R1) subunits

Calcium Signaling Pathway in Fungi

Invasive fungal infections have become frequent in severely immunocompromised individuals, such as transplant, cancer chemotherapy, and HIV-infected patients. Candida spp., Aspergillus spp., and Cryptococcus spp. are the most pervasive fungal pathogens isolated in invasive fungal infections. Calcium signal transduction in fungi has been the focus of extensive study due to its essential role in the survival of fungi. Many findings indicate that various components of the calcium signaling pathway play important roles in fungal physiological processes, mediate stress responses, and promote virulence. Although some of the components in fungal cells are similar to those of mammalian cells, the subtle structural differences have made them a hot area in the development of new antifungal agents or research into new approaches to resisting invasive fungal infections. An increased Ca²⁺ concentration in yeast and filamentous fungal cells affects a wide range of cellular processes, such as cell cycle progression, sporulation, spore germination, oriented hyphal tip growth, hyphal branching, gene expression, and circadian rhythms. This increased concentration also modulates signaling cascades and activates the calcineurin pathway to reduce the Ca²⁺ concentration to the basal level.

Calcineurin as the Target for Antifungal Drug

Calcineurin is responsible for maintaining calcium homeostasis by activating downstream events, and calcineurin-mediated fungal resistance to fungicides constitutes cause for concern. The first evidence for the requirement of calcineurin for virulence came from work on Cryptococcus neoformans followed by other human fungal pathogens, including Candida albicans along with other species of Candida, Cryptococcus and also the filamentous fungal pathogen Aspergillus fumigatus. Furthermore, a role for calcineurin in the pathogenesis of prominent plant fungal pathogens such as Sclerotinia scleotiorum, Botrytis cinerea, Magnaporthe oryzae, Ustilago maydis, and U. hordei have also been described. Interestingly, despite the spectrum of host niches and varied modes of infection of these diverse and morphologically distinct pathogens, calcineurin maintains a conserved role in virulence or pathogenic traits. In a majority of these fungi, calcineurin is required for growth, the transition between morphological states, cation homeostasis, and stress response. Therefore, many studies have searched for antifungal agents by inhibiting the activation of calcineurin. An early study demonstrated that the immunosuppressants cyclosporine (CsA) and tacrolimus (FK506) could bind to the receptor cyclopilin (CyP) and FK506 binding protein (FKBP), respectively, in fungal cells and then interact with the regulatory subunit B of calcineurin to exhibit antifungal activity against Cryptococcus neoformans, which identified calcineurin as a novel antifungal drug target. Calcineurin-mediated resistance has been considered one of the important factors in the failure of clinical treatment of mycoses, and its activation is evoked by the calcium-binding protein calmodulin. Therefore, the inhibition of calmodulin and calcineurin activity in order to reverse antifungal resistance and increase the antifungal activity of existing antifungal drugs has been extensively studied.

Fig.2 Description of the calcium-calcineurin signaling pathway in fungal cells. (Liu, 2015)

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Reference

1. Liu, S.Y.; et al. Components of the calcium-calcineurin signaling pathway in fungal cells and their potential as antifungal targets. Eukaryot Cell. 2015, 14(4): 324-334.

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