Cyclic AMP Pathway Activation and Extracellular Zinc Induce Rapid Intracellular Zinc Mobilization in Candida albicans.

Lasse Kjellerup,Duncan Wilson,Anne-Marie L Winther,Anja T Fuglsang

doi:10.3389/fmicb.2018.00502

Lasse Kjellerup, Duncan Wilson + Show 2 more

Open Access

https://doi.org/10.3389/fmicb.2018.00502

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Abstract

Zinc is an essential micronutrient, required for a range of zinc-dependent enzymes and transcription factors. In mammalian cells, zinc serves as a second messenger molecule. However, a role for zinc in signaling has not yet been established in the fungal kingdom. Here, we used the intracellular zinc reporter, zinbo-5, which allowed visualization of zinc in the endoplasmic reticulum and other components of the internal membrane system in Candida albicans. We provide evidence for a link between cyclic AMP/PKA- and zinc-signaling in this major human fungal pathogen. Glucose stimulation, which triggers a cyclic AMP spike in this fungus resulted in rapid intracellular zinc mobilization and this “zinc flux” could be stimulated with phosphodiesterase inhibitors and blocked via inhibition of adenylate cyclase or PKA. A similar mobilization of intracellular zinc was generated by stimulation of cells with extracellular zinc and this effect could be reversed with the chelator EDTA. However, zinc-induced zinc flux was found to be cyclic AMP independent. In summary, we show that activation of the cyclic AMP/PKA pathway triggers intracellular zinc mobilization in a fungus. To our knowledge, this is the first described link between cyclic AMP signaling and zinc homeostasis in a human fungal pathogen.

Highlights

Zinc is an essential micronutrient for all living organisms and maintaining precise zinc homeostasis is vital for cell survival
Co-staining of C. albicans with the vacuolar membrane stain FM4-64 demonstrated that zinbo-5 is excluded from the vacuole (Figure 1A)
The fungal vacuole can be observed as an apparent indentation by differential interference contrast (DIC) (Figure 1A)

Summary

Introduction

Zinc is an essential micronutrient for all living organisms and maintaining precise zinc homeostasis is vital for cell survival. Candida albicans is an opportunistic fungal pathogen and a major cause of invasive fungal infections, where mortality can reach 40% (Kullberg and Arendrup, 2015), and of vulvovaginal candidiasis, which affects 75% of women of childbearing age (Brown et al, 2012) Metals, such as zinc, play important roles in the control of microbial infections. Depending on the host niche, the immune system can attempt to restrict microbial access to zinc, or to expose them to potentially toxic levels. These processes are known as “nutritional immunity”

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