Comparative transcriptome analysis reveals novel roles of the Ras and cyclic AMP signaling pathways in environmental stress response and antifungal drug sensitivity in Cryptococcus neoformans.
The cyclic AMP (cAMP) pathway plays a central role in the growth, differentiation, and virulence of pathogenic fungi, including Cryptococcus neoformans. Three upstream signaling regulators of adenylyl cyclase (Cac1), Ras, Aca1, and Gpa1, have been demonstrated to control the cAMP pathway in C. neoformans, but their functional relationship remains elusive. We performed a genome-wide transcriptome analysis with a DNA microarray using the ras1Delta, gpa1Delta, cac1Delta, aca1Delta, and pka1Delta pka2Delta mutants. The aca1Delta, gpa1Delta, cac1Delta, and pka1Delta pka2Delta mutants displayed similar transcriptome patterns, whereas the ras1Delta mutant exhibited transcriptome patterns distinct from those of the wild type and the cAMP mutants. Interestingly, a number of environmental stress response genes are modulated differentially in the ras1Delta and cAMP mutants. In fact, the Ras signaling pathway was found to be involved in osmotic and genotoxic stress responses and the maintenance of cell wall integrity via the Cdc24-dependent signaling pathway. Notably, the Ras and cAMP mutants exhibited hypersensitivity to a polyene drug, amphotericin B, without showing effects on ergosterol biosynthesis, which suggested a novel method of antifungal combination therapy. Among the cAMP-dependent gene products that we characterized, two small heat shock proteins, Hsp12 and Hsp122, were found to be involved in the polyene antifungal drug susceptibility of C. neoformans.
Maeng
Shinae
S
Department of Biotechnology, Center for Fungal Pathogenesis, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, 120-749 Seoul, Republic of Korea.
Ko
Young-Joon
YJ
Kim
Gyu-Bum
GB
Jung
Kwang-Woo
KW
Floyd
Anna
A
Heitman
Joseph
J
Bahn
Yong-Sun
YS
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000262:Adenylyl Cyclases / Q000235:genetics; D000935:Antifungal Agents / Q000494:pharmacology; D019187:Cadmium Compounds / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics; D002473:Cell Wall / Q000187:drug effects / Q000235:genetics; D016000:Cluster Analysis; D003224:Congo Red / Q000494:pharmacology; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004149:Dioxoles / Q000494:pharmacology; D015536:Down-Regulation / Q000235:genetics; D025141:Drug Resistance, Fungal / Q000235:genetics / Q000502:physiology*; D005656:Fungal Proteins / Q000235:genetics; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects / Q000502:physiology; D006360:Heat-Shock Proteins / Q000235:genetics; D006918:Hydroxyurea / Q000494:pharmacology; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009997:Osmotic Pressure / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology; D011765:Pyruvaldehyde / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D013431:Sulfates / Q000494:pharmacology; D013481:Superoxides / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000935:Antifungal Agents; D019187:Cadmium Compounds; D018797:Cell Cycle Proteins; D004149:Dioxoles; D005656:Fungal Proteins; D044385:GTP-Binding Protein alpha Subunits; D006360:Heat-Shock Proteins; D011758:Pyrroles; D013431:Sulfates; D013481:Superoxides; D003224:Congo Red; D011765:Pyruvaldehyde; C037123:cadmium sulfate; D008741:Methyl Methanesulfonate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D018631:ras Proteins; D000262:Adenylyl Cyclases; C108339:fludioxonil; D006918:Hydroxyurea