Sur7 promotes plasma membrane organization and is needed for resistance to stressful conditions and to the invasive growth and virulence of Candida albicans.
The human fungal pathogen Candida albicans causes lethal systemic infections because of its ability to grow and disseminate in a host. The C. albicans plasma membrane is essential for virulence by acting as a protective barrier and through its key roles in interfacing with the environment, secretion of virulence factors, morphogenesis, and cell wall synthesis. Difficulties in studying hydrophobic membranes have limited the understanding of how plasma membrane organization contributes to its function and to the actions of antifungal drugs. Therefore, the role of the recently discovered plasma membrane subdomains termed the membrane compartment containing Can1 (MCC) was analyzed by assessing the virulence of a sur7Δ mutant. Sur7 is an integral membrane protein component of the MCC that is needed for proper localization of actin, morphogenesis, cell wall synthesis, and responding to cell wall stress. MCC domains are stable 300-nm-sized punctate patches that associate with a complex of cytoplasmic proteins known as an eisosome. Analysis of virulence-related properties of a sur7Δ mutant revealed defects in intraphagosomal growth in macrophages that correlate with increased sensitivity to oxidation and copper. The sur7Δ mutant was also strongly defective in pathogenesis in a mouse model of systemic candidiasis. The mutant cells showed a decreased ability to initiate an infection and greatly diminished invasive growth into kidney tissues. These studies on Sur7 demonstrate that the plasma membrane MCC domains are critical for virulence and represent an important new target for the development of novel therapeutic strategies. IMPORTANCECandida albicans, the most common human fungal pathogen, causes lethal systemic infections by growing and disseminating in a host. The plasma membrane plays key roles in enabling C. albicans to grow in vivo, and it is also the target of the most commonly used antifungal drugs. However, plasma membrane organization is poorly understood because of the experimental difficulties in studying hydrophobic components. Interestingly, recent studies have identified a novel type of plasma membrane subdomain in fungi known as the membrane compartment containing Can1 (MCC). Cells lacking the MCC-localized protein Sur7 display broad defects in cellular organization and response to stress in vitro. Consistent with this, C. albicans cells lacking the SUR7 gene were more susceptible to attack by macrophages than cells with the gene and showed greatly reduced virulence in a mouse model of systemic infection. Thus, Sur7 and other MCC components represent novel targets for antifungal therapy.
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA.
Lois M
LM
Douglas
Hong X
HX
Wang
Sabine
S
Keppler-Ross
Neta
N
Dean
James B
JB
Konopka
D000818:Animals; D002176:Candida albicans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity*; D002177:Candidiasis / Q000469:parasitology / Q000473:pathology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002470:Cell Survival; D003300:Copper / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D006651:Histocytochemistry; D007668:Kidney / Q000469:parasitology; D008264:Macrophages / Q000469:parasitology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008853:Microscopy; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010588:Phagosomes / Q000469:parasitology; D016019:Survival Analysis; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
D008565:Membrane Proteins; D050505:Mutant Proteins; D037521:Virulence Factors; D003300:Copper