Fig 1.
Left. The molecular ribbon-like structure of Sap2, a major AP of Candida albicans. Note the flexible flaps that control the access to the central region faced and delimited by the two active sites DTGS and DSGT and accommodating an enzyme inhibitor. N-ter is the N-terminus and C-ter the C-terminus of the amino-acid sequence. Right. Sequences of Sap2 and plasmepsin II of Plasmodium falciparum, which is most similar to Sap2 among the APs of eukaryotic microbial pathogens, showing two regions of high similarity (highlighted in red). The identity of the two whole sequences is 28.2% and their similarity 57.4% (FASTA; MBL Swiss-Prot).
Fig 2.
The SAP family of C. albicans contains at least ten proteins with a signal peptide and are secreted, except Sap9 and Sap10, which remain bound to the cell wall.
They are characterized by broad spectrum proteolytic ability and virulence properties that are reported to be differentially expressed at different stages and forms of fungus growth and disease. Sap2 (alike Sap1 and Sap3) is active at acidic pH and is dominantly associated with yeast form of growth while Sap6 (alike Sap4 and Sap5) is more active at neutral to slightly alkaline pH Together with the dominant Sap5, Sap6 has been associated with hyphal growth. For details, see [7] and [28].
Fig 3.
The proposed view of Sap-induced inflammasome activation and inflammasome-dependent cytokine production.
Sap2 and Sap6 activate the NLRP3 inflammasome pathway through an early cascade of events, causing upstream NLRP3 inflammasome activation and downstream caspase-1-mediated cytokine production. Late events depend on Sap endocytosis inducing the translocation of NF-κB (p50/p65) into the nucleus, pro-IL-1β and pro-IL-18 synthesis, then (through type I IFN production) caspase-11 activation that cooperates with the NLRP3 inflammasome in triggering downstream caspase-1-mediated cytokine production. For details about this proposed scheme of Sap/inflammasome/caspases activation, see [38], [39], and [42].