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Autophagy is mainly a catabolic process, which is used to cope with nutrient deficiency and various stress conditions. Human environment often imposes various stresses on  Cryptococcus neoformans , a major fungal pathogen of immunocompromised individuals; therefore, autophagic response of  C. neoformans  to these stresses often determines its survival in the host. However, a systematic study on how autophagy related ( ATG ) genes influence on autophagic flux, virulence, stress response and pathogenicity of  C. neoformans  is lacking. In this study, 22  ATG -deficient strains were constructed to investigate their roles in virulence, pathogenesis, stress response, starvation tolerance and autophagic flux in  C. neoformans . Our results showed that Atg6 and Atg14-03 significantly affect the growth of  C. neoformans  at 37°C and laccase production. Additionally,  atg2 Δ and  atg6 Δ strains were sensitive to oxidative stress caused by hydrogen peroxide. Approximately half of the  atg Δ strains displayed higher sensitivity to 1.5 M NaCl and remarkably lower virulence in the  Galleria mellonella  model than the wild type. Autophagic flux in  C. neoformans  was dependent on the Atg1-Atg13, Atg5-Atg12-Atg16, and Atg2-Atg18 complexes and Atg11. Cleavage of the green fluorescent protein (GFP) from Atg8 was difficult to detect in these autophagy defective mutants; however, it was detected in the  atg3 Δ,  atg4 Δ,  atg6 Δ and  atg14 Δ strains. Additionally, no homologs of  Saccharomyces cerevisiae ATG10  were detected in  C. neoformans . Our results indicate that these  ATG  genes contribute differentially to carbon and nitrogen starvation tolerance in  C. neoformans  compared with  S. cerevisiae . Overall, this study advances our knowledge of the specific roles of  ATG  genes in  C. neoformans .

frontiers in microbiology

Conserved Autophagy Pathway Contributes to Stress Tolerance and Virulence and Differentially Controls Autophagic Flux Upon Nutrient Starvation in Cryptococcus neoformans