Cytochrome c regulates hyphal morphogenesis by interfering with cAMP-PKA signaling in Candida albicans
Guisheng Zeng,
Xiaoli Xu,
Yee Jiun Kok,
Fu-Sheng Deng,
Eve Wai Ling Chow,
Jiaxin Gao,
Xuezhi Bi,
Yue Wang
Affiliations
Guisheng Zeng
A∗STAR Infectious Diseases Labs (A∗STAR ID Labs), Agency for Science, Technology and Research (A∗STAR), 8A Biomedical Grove, #05-13 Immunos, Singapore 138648, Singapore; Corresponding author
Xiaoli Xu
A∗STAR Infectious Diseases Labs (A∗STAR ID Labs), Agency for Science, Technology and Research (A∗STAR), 8A Biomedical Grove, #05-13 Immunos, Singapore 138648, Singapore
Yee Jiun Kok
Bioprocessing Technology Institute, 20 Biopolis Way, #06-01 Centros, Singapore 138668, Singapore
Fu-Sheng Deng
Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei 10617, Taiwan
Eve Wai Ling Chow
A∗STAR Infectious Diseases Labs (A∗STAR ID Labs), Agency for Science, Technology and Research (A∗STAR), 8A Biomedical Grove, #05-13 Immunos, Singapore 138648, Singapore
Jiaxin Gao
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Xuezhi Bi
Bioprocessing Technology Institute, 20 Biopolis Way, #06-01 Centros, Singapore 138668, Singapore; Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore
Yue Wang
A∗STAR Infectious Diseases Labs (A∗STAR ID Labs), Agency for Science, Technology and Research (A∗STAR), 8A Biomedical Grove, #05-13 Immunos, Singapore 138648, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; Corresponding author
Summary: In the human fungal pathogen Candida albicans, invasive hyphal growth is a well-recognized virulence trait. We employed transposon-mediated genome-wide mutagenesis, revealing that inactivating CTM1 blocks hyphal growth. CTM1 encodes a lysine (K) methyltransferase, which trimethylates cytochrome c (Cyc1) at K79. Mutants lacking CTM1 or expressing cyc1K79A grow as yeast under hyphae-inducing conditions, indicating that unmethylated Cyc1 suppresses hyphal growth. Transcriptomic analyses detected increased levels of the hyphal repressor NRG1 and decreased levels of hyphae-specific genes in ctm1Δ/Δ and cyc1K79A mutants, suggesting cyclic AMP (cAMP)-protein kinase A (PKA) signaling suppression. Co-immunoprecipitation and in vitro kinase assays demonstrated that unmethylated Cyc1 inhibits PKA kinase activity. Surprisingly, hyphae-defective ctm1Δ/Δ and cyc1K79A mutants remain virulent in mice due to accelerated proliferation. Our results unveil a critical role for cytochrome c in maintaining the virulence of C. albicans by orchestrating proliferation, growth mode, and metabolism. Importantly, this study identifies a biological function for lysine methylation on cytochrome c.
