Abstract
The Mkt1–Pbp1 complex promotes mating-type switching by regulating the translation of HO mRNA in Saccharomyces cerevisiae. Here, we performed in vivo immunoprecipitation assays and mass spectrometry analyses in the human fungal pathogen Cryptococcus neoformans to show that Pbp1, a poly(A)-binding protein-binding protein, interacts with Mkt1 containing a PIN like-domain. Association of Pbp1 with Mkt1 was confirmed by co-immunoprecipitation assays. Results of spot dilution growth assays showed that unlike pbp1 deletion mutant strains, mkt1 deletion mutant strains were not resistant to heat stress compared with wild-type. However, similar to the pbp1 deletion mutant strains, the mkt1 deletion mutants exhibited both, defective dikaryotic hyphal production and reduced pheromone gene (MFα1) expression during mating. In addition, deletion of mkt1 caused attenuated virulence in a murine intranasal inhalation model. Taken together, our findings reveal that Mkt1 plays a crucial role in sexual reproduction and virulence in C. neoformans.
Highlights
Cryptococcus neoformans is an opportunistic human pathogenic fungus that causes cryptococcosis, including cryptococcal meningoencephalitis and pulmonary cryptococcosis (Chang et al, 2006; Bratton et al, 2012)
Pbp1 is a putative calcineurin target associated with sexual reproduction and virulence in C. neoformans
Because Pbp1 is required for proper sexual reproduction in C. neoformans, we examined whether Mkt1 is required for sexual reproduction in C. neoformans
Summary
Cryptococcus neoformans is an opportunistic human pathogenic fungus that causes cryptococcosis, including cryptococcal meningoencephalitis and pulmonary cryptococcosis (Chang et al, 2006; Bratton et al, 2012). Cryptococcus is the leading cause of adult meningoencephalitis in Sub-Saharan Africa and Southeast Asia and is associated with a high mortality rate (Armstrong-James et al, 2014; Bongomin et al, 2017; Rajasingham et al, 2017). While cryptococcal meningoencephalitis results in a high mortality rate, treatment of cryptococcosis is limited by toxicity of and resistance to current antifungal agents (Perfect et al, 2010; Fisher et al, 2018). A comprehensive understanding of biological mechanisms underlying fungal pathogenicity is necessary to develop novel antifungal agents or therapies. Multiple recent studies have conducted comprehensive analyses to obtain insights into the pathogenicity of C. neoformans (Liu et al, 2008; Jung et al, 2015; Maier et al, 2015; Gish et al, 2016; Lee et al, 2016)
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