Tripeptidyl peptidase II links intracellular amino acids homeostasis with immune response through glycolytic pathway (IRM9P.463)

Abstract

Abstract Proteasomes and lysosomes constitute the major cellular proteolytic systems that not only remove unfolded, damaged, or unnecessary proteins, but also provide an essential supply of free amino acids for energy and new protein synthesis. Tripeptidyl peptidase II (TPP2) is a required component of the proteasome-ubiquitin protein degradation pathway. The patients lack of TPP2 manifest a combined immunodeficiency with recurrent infections, severe autoimmunity, and neurodevelopmental delay. We observed a marked increase in lysosome number and lysosomal proteolytic activity in patient cells lacking TPP2 activity. Upregulated lysosomes compensated for deficient amino acid homeostasis when TPP2 was absent. We confirmed these results in Tpp2 knockout mice and in normal human cells treated with butabindide, a selective chemical inhibitor of TPP2. However, we also found that the overabundant lysosomes exerted a pathogenic effect in which key glycolytic enzymes including hexokinase II (HKII), were consumed. The resulting decreased glycolytic potential in TPP2 defective cells selectively attenuated the production of several immunomodulatory cytokines such as IFN-γ and IL-1β, whose production require aerobic glycolysis. Taken together, our data reveal the vital role of TPP2 in amino acid supply and unveil the intimate homeostatic balance between lysosome number, amino acid level, and glycolysis in mammalian cells.