Abstract
Glycosylphosphatidyl inositol anchored proteins (GPI-APs) on fungal cell wall are essential for invasive infections. While the function of inositol deacylation of GPI-APs in mammalian cells has been previously characterized the impact of inositol deacylation in fungi and implications to host infection remains largely unexplored. Herein we describe our identification of BST1, an inositol deacylase of GPI-Aps in Candida albicans, was critical for GPI-APs cell wall attachment and host infection. BST1-deficient C. albicans (bst1Δ/Δ) was associated with severely impaired cell wall anchorage of GPI-APs and subsequen unmasked β-(1,3)-glucan. Consistent with the aberrant cell wall structures, bst1Δ/Δ strain did not display an invasive ability and could be recognized more efficiently by host immune systems. Moreover, BST1 null mutants or those expressing Bst1 variants did not display inositol deacylation activity and exhibited severely attenuated virulence and reduced organic colonization in a murine systemic candidiasis model. Thus, Bst1 can facilitate cell wall anchorage of GPI-APs in C. albicans by inositol deacylation, and is critical for host invasion and immune escape.
Highlights
Linked to polysaccharides are mannoproteins localizing on the outermost cell wall
The majority of Als1p from bst1Δ/Δ strain remained partitioned into the detergent phase following phosphoinositide-phospholipase C (PI-PLC) treatment, suggesting that glycosylphosphatidyl inositol anchored proteins (GPI-APs) from bst1Δ/Δ strain were resistant to PI-PLC (Fig. 1B)
The inositol moiety of GPI is acylated at an early step in GPI biosynthesis, which is essential for the generation of mature GPI capable of proteins attachment in fungi
Summary
As major covalently-linked mannoproteins, glycosylphosphatidyl inositol anchored proteins (GPI-APs) attach to cell wall β-(1,6)-glucan through GPI remnant[5]. Previous studies have indicated that GPI-APs contribute to cell wall integrity, biofilm formation, adherence to host cells and abiotic medical devices, invasion of epithelial layers, and iron acquisition[6]. These studies highlighted the effects associated with deleting a GPI-AP, such as Ecm33p, noting reduced virulence of fungi[7]. We first demonstrated that Bst[1] can facilitate GPI-APs targeting to cell wall by inositol deacylation in human pathogen C. albicans. Our results demonstrate that C. albicans with defective inositol deacylase exhibit impaired invasive ability and enhanced recognition by host immune systems
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