Cryptococcus neoformans, a global fungal meningitis pathogen, employs the unfolded protein response pathway. This pathway, which consists of an evolutionarily conserved Ire1 kinase/endoribonuclease and a unique transcription factor (Hxl1), modulates the endoplasmic reticulum stress response and pathogenicity. Here, we report that the unfolded protein response pathway governs sexual and unisexual differentiation of C. neoformans in an Ire1-dependent but Hxl1-independent manner. The ire1Δ mutants showed defects in sexual mating, with reduced cell fusion and pheromone-mediated formation of the conjugation tube. Unexpectedly, these mating defects did not result from defective pheromone production because expression of the mating pheromone gene (MFα1) was strongly induced in the ire1Δ mutant. Ire1 controls sexual differentiation by modulating the function of the molecular chaperone Kar2 and by regulating mating-induced localisation of mating pheromone transporter (Ste6) and receptor (Ste3/Cprα). Deletion of IRE1, but not HXL1, also caused significant defects in unisexual differentiation in a Kar2-independent manner. Moreover, we showed that Rim101 is a novel downstream factor of Ire1 for production of the capsule, which is a unique structural determinant of C. neoformans virulence. Therefore, Ire1 uniquely regulates fungal development and differentiation in an Hxl1-independent manner.
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