Pneumocystis carinii BCK1 functions in a mitogen-activated protein kinase cascade regulating fungal cell-wall assembly.
Pneumocystis pneumonia remains the most common AIDS-defining opportunistic infection in people with HIV. The process by which Pneumocystis carinii constructs its cell wall is not well known, although recent studies reveal that molecules such as beta-1-3-glucan synthetase (GSC1) and environmental pH-responsive genes such as PHR1 are important for cell-wall integrity. In closely related fungi, a specific mitogen-activated protein kinase (MAPK) cascade regulates cell-wall assembly in response to elevated temperature. The upstream mitogen-activated protein kinase kinase kinase (MAPKKK, or MEKK), BCK1, is an essential component in this pathway for maintaining cell-wall integrity and preventing fungal cell lysis. We have identified a P. carinii MEKK gene and have expressed it in Saccharomyces cerevisiae to gain insights into its function. The P. carinii MEKK, PCBCK1, corrects the temperature-sensitive cell lysis defect of bck1Delta yeast. Further, at elevated temperature PCBCK1 restored the signaling defect in bck1Delta yeast to maintain expression of the temperature-inducible beta-1-3-glucan synthetase gene, FKS2. PCBCK1, as a functional kinase, is capable of autophosphorylation and substrate phosphorylation. Since glucan machinery is not present in mammals, a better understanding of this pathway in P. carinii might aid in the development of novel medications which interfere with the integrity of the Pneumocystis cell wall.
Thomas
Charles F
CF
Thoracic Diseases Research Unit, Division of Pulmonary, Critical Care and Internal Medicine, Department of Medicine, 826 Stabile Building, Mayo Clinic and Foundation, Rochester, MN 55905, USA. thomas.charles@mayo.edu
Vohra
Pawan K
PK
Park
John G
JG
Puri
Veenu
V
Limper
Andrew H
AH
Kottom
Theodore J
TJ
D001483:Base Sequence; D002473:Cell Wall / Q000378:metabolism*; D003001:Cloning, Molecular; D017124:Conserved Sequence; D005800:Genes, Fungal / Q000235:genetics; D005964:Glucosyltransferases; D020930:MAP Kinase Kinase Kinases; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D008969:Molecular Sequence Data; D009154:Mutation; D011010:Pneumocystis / Q000201:enzymology*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D016415:Sequence Alignment; D013696:Temperature
D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; D005964:Glucosyltransferases; C095724:GSC2 protein, S cerevisiae; C476643:BCK1 protein, Pneumocystis carinii; D020930:MAP Kinase Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases