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Proteasomes and lysosomes constitute the major cellular systems that catabolize proteins to recycle free amino acids for energy and new protein synthesis. Tripeptidyl peptidase II (TPPII) is a large cytosolic proteolytic complex that functions in tandem with the proteasome-ubiquitin protein degradation pathway. We found that autosomal recessive TPP2 mutations cause recurrent infections, autoimmunity, and neurodevelopmental delay in humans. We show that a major function of TPPII in mammalian cells is to maintain amino acid levels and that TPPII-deficient cells compensate by increasing lysosome number and proteolytic activity. However, the overabundant lysosomes derange cellular metabolism by consuming the key glycolytic enzyme hexokinase-2 through chaperone-mediated autophagy. This reduces glycolysis and impairs the production of effector cytokines, including IFN-γ and IL-1β. Thus, TPPII controls the balance between intracellular amino acid availability, lysosome number, and glycolysis, which is vital for adaptive and innate immunity and neurodevelopmental health.

Original publication

DOI

10.1016/j.cell.2014.12.001

Type

Journal article

Journal

Cell

Publication Date

18/12/2014

Volume

159

Pages

1578 - 1590

Keywords

Adaptive Immunity, Amino Acid Sequence, Aminopeptidases, Animals, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Female, Glycolysis, Humans, Immunity, Innate, Immunologic Deficiency Syndromes, Lysosomes, Male, Models, Molecular, Molecular Sequence Data, Pedigree, Proteolysis, Sequence Alignment, Serine Endopeptidases