The Snf1-activating kinase Sak1 is a key regulator of metabolic adaptation and in vivo fitness of Candida albicans.
The metabolic flexibility of the opportunistic fungal pathogen Candida albicans is important for colonisation and infection of different host niches. Complex regulatory networks, in which protein kinases play central roles, link metabolism and other virulence-associated traits, such as filamentous growth and stress resistance, and thereby control commensalism and pathogenicity. By screening a protein kinase deletion mutant library that was generated in the present work using an improved SAT1 flipper cassette, we found that the previously uncharacterised kinase Sak1 is a key upstream activator of the protein kinase Snf1, a highly conserved regulator of nutrient stress responses that is essential for viability in C. albicans. The sak1Δ mutants failed to grow on many alternative carbon sources and were hypersensitive to cell wall/membrane stress. These phenotypes were mirrored in mutants lacking other subunits of the SNF1 complex and partially compensated by a hyperactive form of Snf1. Transcriptional profiling of sak1Δ mutants showed that Sak1 ensures basal expression of glyoxylate cycle and gluconeogenesis genes even in glucose-rich media and thereby contributes to the metabolic plasticity of C. albicans. In a mouse model of gastrointestinal colonisation, sak1Δ mutants were rapidly outcompeted by wild-type cells, demonstrating that Sak1 is essential for the in vivo fitness of C. albicans.
Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
Bernardo
B
Ramírez-Zavala
Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
Austin
A
Mottola
Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
Julia
J
Haubenreißer
Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
Sabrina
S
Schneider
Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Germany.
Stefanie
S
Allert
Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Germany.
Sascha
S
Brunke
Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
Knut
K
Ohlsen
Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Germany.|Friedrich Schiller University, Jena, Germany.|Center for Sepsis Control and Care (CSCC), Jena, Germany.
Bernhard
B
Hube
Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
Joachim
http://orcid.org/0000-0003-4227-8687
J
Morschhäuser
D000818:Animals; D002176:Candida albicans / Q000235:genetics / Q000378:metabolism*; D002244:Carbon / Q000378:metabolism; D005260:Female; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D015723:Gene Library; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D014774:Virulence
D005656:Fungal Proteins; D002244:Carbon; D011494:Protein Kinases; C071570:SNF1-related protein kinases; D017346:Protein Serine-Threonine Kinases