Exposure of Candida albicans β (1,3)-glucan is promoted by activation of the Cek1 pathway

PLoS Genet. 2019 Jan 31;15(1):e1007892. doi: 10.1371/journal.pgen.1007892. eCollection 2019 Jan.

Abstract

Candida albicans is among the most common causes of human fungal infections and is an important source of mortality. C. albicans is able to diminish its detection by innate immune cells through masking of β (1,3)-glucan in the inner cell wall with an outer layer of heavily glycosylated mannoproteins (mannan). However, mutations or drugs that disrupt the cell wall can lead to exposure of β (1,3)-glucan (unmasking) and enhanced detection by innate immune cells through receptors like Dectin-1, the C-type signaling lectin. Previously, our lab showed that the pathway for synthesizing the phospholipid phosphatidylserine (PS) plays a role in β (1,3)-glucan masking. The homozygous PS synthase knockout mutant, cho1Δ/Δ, exhibits increased exposure of β (1,3)-glucan. Several Mitogen Activated Protein Kinase (MAPK) pathways and their upstream Rho-type small GTPases are important for regulating cell wall biogenesis and remodeling. In the cho1Δ/Δ mutant, both the Cek1 and Mkc1 MAPKs are constitutively activated, and they act downstream of the small GTPases Cdc42 and Rho1, respectively. In addition, Cdc42 activity is up-regulated in cho1Δ/Δ. Thus, it was hypothesized that activation of Cdc42 or Rho1 and their downstream kinases cause unmasking. Disruption of MKC1 does not decrease unmasking in cho1Δ/Δ, and hyperactivation of Rho1 in wild-type cells increases unmasking and activation of both Cek1 and Mkc1. Moreover, independent hyperactivation of the MAP kinase kinase kinase Ste11 in wild-type cells leads to Cek1 activation and increased β (1,3)-glucan exposure. Thus, upregulation of the Cek1 MAPK pathway causes unmasking, and may be responsible for unmasking in cho1Δ/Δ.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CDPdiacylglycerol-Serine O-Phosphatidyltransferase / genetics*
  • Candida albicans / genetics*
  • Cell Wall / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Fungal Proteins / genetics*
  • Gene Expression Regulation, Fungal
  • Gene Knockout Techniques
  • Guanosine Triphosphate / genetics
  • Humans
  • Lectins, C-Type / genetics
  • MAP Kinase Kinase Kinases / genetics*
  • MAP Kinase Signaling System / genetics
  • Mitogen-Activated Protein Kinase 3 / genetics*
  • Mitogen-Activated Protein Kinases / genetics
  • beta-Glucans / chemistry
  • beta-Glucans / metabolism
  • cdc42 GTP-Binding Protein / genetics

Substances

  • Fungal Proteins
  • Lectins, C-Type
  • beta-Glucans
  • dectin 1
  • CEK1 protein, Candida albicans
  • Guanosine Triphosphate
  • MKC1 protein, Candida albicans
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • CDPdiacylglycerol-Serine O-Phosphatidyltransferase
  • cdc42 GTP-Binding Protein