AUTHOR=Zhao Xueru , Feng Weijia , Zhu Xiangyang , Li Chenxi , Ma Xiaoyu , Li Xin , Zhu Xudong , Wei Dongsheng 

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

JOURNAL=Frontiers in Microbiology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2019.02690

DOI=10.3389/fmicb.2019.02690

ISSN=1664-302X

ABSTRACT=<p>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 <italic>Cryptococcus neoformans</italic>, a major fungal pathogen of immunocompromised individuals; therefore, autophagic response of <italic>C. neoformans</italic> to these stresses often determines its survival in the host. However, a systematic study on how autophagy related (<italic>ATG</italic>) genes influence on autophagic flux, virulence, stress response and pathogenicity of <italic>C. neoformans</italic> is lacking. In this study, 22 <italic>ATG</italic>-deficient strains were constructed to investigate their roles in virulence, pathogenesis, stress response, starvation tolerance and autophagic flux in <italic>C. neoformans</italic>. Our results showed that Atg6 and Atg14-03 significantly affect the growth of <italic>C. neoformans</italic> at 37°C and laccase production. Additionally, <italic>atg2</italic>Δ and <italic>atg6</italic>Δ strains were sensitive to oxidative stress caused by hydrogen peroxide. Approximately half of the <italic>atg</italic>Δ strains displayed higher sensitivity to 1.5 M NaCl and remarkably lower virulence in the <italic>Galleria mellonella</italic> model than the wild type. Autophagic flux in <italic>C. neoformans</italic> 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 <italic>atg3</italic>Δ, <italic>atg4</italic>Δ, <italic>atg6</italic>Δ and <italic>atg14</italic>Δ strains. Additionally, no homologs of <italic>Saccharomyces cerevisiae ATG10</italic> were detected in <italic>C. neoformans</italic>. Our results indicate that these <italic>ATG</italic> genes contribute differentially to carbon and nitrogen starvation tolerance in <italic>C. neoformans</italic> compared with <italic>S. cerevisiae</italic>. Overall, this study advances our knowledge of the specific roles of <italic>ATG</italic> genes in <italic>C. neoformans</italic>.</p>