N-Acetylglucosamine-Induced Cell Death in Candida albicans and Its Implications for Adaptive Mechanisms of Nutrient Sensing in Yeasts.
Single-celled organisms have different strategies to sense and utilize nutrients in their ever-changing environments. The opportunistic fungal pathogen Candida albicans is a common member of the human microbiota, especially that of the gastrointestinal (GI) tract. An important question concerns how C. albicans gained a competitive advantage over other microbes to become a successful commensal and opportunistic pathogen. Here, we report that C. albicans uses N-acetylglucosamine (GlcNAc), an abundant carbon source present in the GI tract, as a signal for nutrient availability. When placed in water, C. albicans cells normally enter the G0 phase and remain viable for weeks. However, they quickly lose viability when cultured in water containing only GlcNAc. We term this phenomenon GlcNAc-induced cell death (GICD). GlcNAc triggers the upregulation of ribosomal biogenesis genes, alterations of mitochondrial metabolism, and the accumulation of reactive oxygen species (ROS), followed by rapid cell death via both apoptotic and necrotic mechanisms. Multiple pathways, including the conserved cyclic AMP (cAMP) signaling and GlcNAc catabolic pathways, are involved in GICD. GlcNAc acts as a signaling molecule to regulate multiple cellular programs in a coordinated manner and therefore maximizes the efficiency of nutrient use. This adaptive behavior allows C. albicans' more efficient colonization of the gut.


OBJECTIVE
The ability to rapidly and appropriately respond to nutrients in the environment is crucial to free-living microorganisms. To maximize the use of available nutrients, microorganisms often use a limiting nutritional component as a signal to coordinate multiple biological processes. The human fungal pathogen Candida albicans uses N-acetylglucosamine (GlcNAc) as a signal for the availability of external nutrient resources. GlcNAc induces rapid cell death in C. albicans due to the constitutive activation of oxidative metabolism and accumulation of reactive oxygen species (ROS), and multiple pathways are involved in its regulation. This study sheds light on the mechanisms of niche specialization of pathogenic fungi and raises the possibility that this cell death pathway could be an unexplored therapeutic target.
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Han
H
Du
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Guobo
G
Guan
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Xiaoling
X
Li
Department of Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, Merced, California, USA.
Megha
M
Gulati
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Li
L
Tao
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China University of Chinese Academy of Sciences, Beijing, China.
Chengjun
C
Cao
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA.
Alexander D
AD
Johnson
Department of Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, Merced, California, USA.
Clarissa J
CJ
Nobile
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China huanggh@im.ac.cn.
Guanghua
G
Huang
D000117:Acetylglucosamine / Q000378:metabolism*; D002176:Candida albicans / Q000187:drug effects* / Q000502:physiology*; D016923:Cell Death; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects*; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA
D000117:Acetylglucosamine