The Role of Secretory Pathways in Candida albicans Pathogenesis

Abstract

Candida albicans is a fungus that is a commensal organism and a member of the normal human microbiota. It has the ability to transition into an opportunistic invasive pathogen. Attributes that support pathogenesis include secretion of virulence-associated proteins, hyphal formation, and biofilm formation. These processes are supported by secretion, as defined in the broad context of membrane trafficking. In this review, we examine the role of secretory pathways in Candida virulence, with a focus on the model opportunistic fungal pathogen, Candida albicans.

Keywords: Candida albicans; biofilm; filamentation; pathogenesis; secretion; trafficking; virulence.

Figure 1

Schematic of antegrade secretory traffic C. albicans. In this simplified diagram, two branches of the exocytic pathway are shown: the general secretory pathway and the pre-vacuolar branch of the exocytic pathway. Multiple endocytic and retrograde sorting pathways are not shown in this diagram. In the pre-vacuolar secretory pathway, Vps1p is a dynamin-like GTPase that mediates vesicle budding from the late Golgi. Vps4p is an AAA-type ATPase that mediates vesicle budding from the pre-vacuolar compartment (PVC). Pep12p is a pre-vacuolar t-SNARE (soluble N-ethylmaleimide-sensitive factor activating protein receptor) and Vam3p is a vacuolar t-SNARE. The exocyst complex regulates the critical final steps of polarized secretion just prior to exocytosis, shown in greater detail in Figure 2.

Figure 2

A model of the exocyst and SNARE complex. The exocyst is an octameric protein complex that marks the sites of exocytosis by facilitating the tethering and fission of late secretory vesicles to the plasma membrane. Based on data from S. cerevisiae, Sec3 and Exo70 proteins directly associate with phosphatidylinositol 4,5-bisphosphates in the plasma membrane. Assembly of the remaining exocyst components occurs as secretory vesicles arrive. The exocyst then functions to tether secretory vesicles to the exocytic sites and regulate SNARE assembly. The exocyst component Exo84 also interacts directly with Sro7 protein, which is a downstream effector of the small Rab-like GTPase Sec4, which regulates post-Golgi secretion. Additional regulation of the exocyst complex is performed by the Rho GTPases: Rho1, Rho3 and Cdc42. Snc1/2 proteins are the v-SNARES and Sso1/2 and Sec9 proteins are the t-SNARES required for final vesicle fusion to the plasma membrane just preceding exocytosis.

Figure 3

Clathrin-mediated and clathrin-independent endocytosis in yeast. Clathrin-mediated endocytosis is a highlyorchestrated, step-wise process that begins at the plasma membrane and leads to delivery of endocytic cargo through the endosomal pathway to the PVC (pre-vacuolar compartment). The clathrin-independent has fewer identified proteins but also leads through the endosomal pathway to the PVC. Proteins shown in bold have been studied in C. albicans, others are orthologous to ones studied in S. cerevisiae. Little is known about the role of clathrin-independent endocytosis in C. albicans.