Modeling human supramolecular organizing centers and regulated cell death pathways involved in innate immunity in Saccharomyces cerevisiae

Zusammenfassung

The innate immune system represents the first defense barrier against pathogens and cellular perturbations in higher eukaryotes. Its response relies on SMOCs (supramolecular organizing centers):complexes composed of a receptor, adaptor, and effector protein that are recruited sequentially under the proper stimulus to coordinate the cellular response. This unique system helps to amplify the signal,although their functioning and regulation are still under study. The NLRP3 [NLR [NOD (nucleotideoligomerization domain)-like receptor] family pyrin domain-containing 3] inflammasome and theFas/CD95 (cluster of differentiation 95) DISC (death-inducing signaling complex), which regulate pyroptosis and extrinsic apoptosis, respectively, constitute two great examples of human SMOCs. Besides, when cellular damage exceeds a threshold, the innate immune system promotes the induction of regulated-cell death programs to protect the organism, among which pyroptosis and necroptosis play a prominent role. Their effectors, GSDMD (Gasdermin D) and MLKL (mixed lineagekinase domain like pseudokinase), respectively, are pore-forming proteins that trigger the disruptionof the plasma membrane and, thus, cell death. They differ in their mechanism of activation, byproteolysis and phosphorylation, respectively. However, they also target intracellular compartmentsby a mechanism not fully understood. Saccharomyces cerevisiae has long been used as a eukaryotic model to characterize proteins associated with human diseases, including those involved in the innate immune response, due to the numerous advantages provided by this microorganism and the high degree of conservation between human and yeast cellular structures and signaling pathways...