Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells

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Abstract
Candida albicans is the most common cause of hematogenously disseminated and oropharyngeal candidiasis. Both of these diseases are characterized by fungal invasion of host cells. Previously, we have found that C. albicans hyphae invade endothelial cells and oral epithelial cells in vitro by inducing their own endocytosis. Therefore, we set out to identify the fungal surface protein and host cell receptors that mediate this process. We found that the C. albicans Als3 is required for the organism to be endocytosed by human umbilical vein endothelial cells and two different human oral epithelial lines. Affinity purification experiments with wild-type and an als3Δ/als3Δ mutant strain of C. albicans demonstrated that Als3 was required for C. albicans to bind to multiple host cell surface proteins, including N-cadherin on endothelial cells and E-cadherin on oral epithelial cells. Furthermore, latex beads coated with the recombinant N-terminal portion of Als3 were endocytosed by Chinese hamster ovary cells expressing human N-cadherin or E-cadherin, whereas control beads coated with bovine serum albumin were not. Molecular modeling of the interactions of the N-terminal region of Als3 with the ectodomains of N-cadherin and E-cadherin indicated that the binding parameters of Als3 to either cadherin are similar to those of cadherin–cadherin binding. Therefore, Als3 is a fungal invasin that mimics host cell cadherins and induces endocytosis by binding to N-cadherin on endothelial cells and E-cadherin on oral epithelial cells. These results uncover the first known fungal invasin and provide evidence that C. albicans Als3 is a molecular mimic of human cadherins. The fungus Candida albicans is usually a harmless colonizer of human mucosal surfaces. In the mouth, it can cause oropharyngeal candidiasis, also called thrush. In hospitalized and immunocompromised patients, C. albicans can enter the blood stream and be carried throughout the body to cause a disseminated infection, which is associated with a mortality rate of up to 40%. The organism invades the epithelial cell lining of the mouth during oropharyngeal candidiasis and invades the endothelial cell lining of the blood vessels during disseminated candidiasis. We discovered that Als3, a protein expressed on the surface of C. albicans, is required for this invasion process. Cadherins on the surface of human cells normally bind other cadherins for adhesion and signaling; however, we found that Als3 also binds to cadherins on endothelial cells and oral epithelial cells, and this binding induces these host cells to take up the fungus. The structure of Als3 is predicted to be quite similar to that of the two cadherins studied, and the parameters of the binding of Als3 to either cadherin are similar to those of cadherin–cadherin binding. These results suggest that Als3 is a functional and structural mimic of human cadherins, and provide new insights into how C. albicans invades host cells.