Autophagy and LAP in the Fight against Fungal Infections: Regulation and Therapeutics

Figure 1

Overview of the LAP pathway during Aspergillus fumigatus infection. (1) Cell wall swelling of resting Aspergillus conidia (exposure of carbohydrate molecules, such as β-glucan) activates innate immune responses in host phagocytes. (2) Pattern recognition receptors (PPRs) on phagocytes (Dectin-1, TLRs) recognize β-glucan and internalize it through phagocytosis. During phagocytosis, swollen Aspergillus conidia trigger the Dectin-1/Syk kinase complex. (3) Subsequent activation of LAP occurs by recruitment of the class III PI3K complex (Rubicon/UVRAG/VPS34/Beclin-1) to the single-membrane phagosome. (4) The class III PI3K complex generates PI(3)P that localizes to phagosome with subsequent stabilization of the NOX2 complex by Rubicon and PI(3)P. (5) Complete assembly of the NOX2 NADPH oxidase complex is capable in optimal ROS production. (6) PI(3)P formation and ROS production lead to the recruitment of the downstream Atg5/Atg12/Atg16L1 conjugation complex, as well as of Atg7, Atg3, and Atg4, all of which are critical for the lipidation of LC3 (conjugation of LC3I to PE to form LC3II). (7) LAPosome maturation requires LC3II deposition and DAPK1 localization for anti-inflammatory activity. Finally, (8) fusion with LAMP-1-lysosome and (9) phagolysosome formation with fungal killing occur.