The unfolded protein response (UPR) pathway, consisting of the evolutionarily conserved Ire1 kinase/endonuclease and the bZIP transcription factor Hxl1, is critical for the pathogenicity of Cryptococcus neoformans; however, its role remains unknown in other pathogenic Cryptococcus species. Here, we investigated the role of the UPR pathway in C. deuterogattii, which causes pneumonia and systemic cryptococcosis, even in immunocompetent individuals. In response to ER stress, C. deuterogattii Ire1 triggers unconventional splicing of HXL1 to induce the expression of UPR target genes such as KAR2, DER1, ALG7, and ERG29. Furthermore, C. deuterogattii Ire1 is required for growth at mammalian body temperature, similar to C. neoformans Ire1. However, deletion of HXL1 does not significantly affect the growth of C. deuterogattii at 37 °C, which is in contrast to the indispensable role of HXL1 in the growth of C. neoformans at 37 °C. Nevertheless, both C. deuterogattii ire1Δ and hxl1Δ mutants are avirulent in a murine model of systemic cryptococcosis, suggesting that a non-Thermotolerance phenotypic trait also contributes to the role of the UPR pathway in the virulence of pathogenic Cryptococcus species. In conclusion, the UPR pathway plays redundant and distinct roles in the virulence of members of the pathogenic Cryptococcus species complex.
Bibliographical noteFunding Information:
This work was supported by National Research Foundation of Korea grants (2016R1E1A1A01943365) and in part by the General International Collaborative R&D program funded by Ministry of Trade, Industry and Energy (MOTIE) in Republic of Korea (N0001720)(to Y.-S.B.). This work was also supported in part by NIH/NIAD R37 MERIT award AI39115-20 and NIH/NIAID R01 award AI50113-14 (to J.H.).
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