Dual proteolytic pathways govern glycolysis and immune competence.

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Item Type:	Article
Title:	Dual proteolytic pathways govern glycolysis and immune competence.
Creators Name:	Lu, W., Zhang, Y., McDonald, D.O., Jing, H., Carroll, B., Robertson, N., Zhang, Q., Griffin, H., Sanderson, S., Lakey, J.H., Morgan, N.V., Reynard, L.N., Zheng, L., Murdock, H.M., Turvey, S.E., Hackett, S.J., Prestidge, T., Hall, J.M., Cant, A.J., Matthews, H.F., Koref, M.F.S., Simon, A.K., Korolchuk, V.I., Lenardo, M.J., Hambleton, S. and Su, H.C.
Abstract:	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.
Keywords:	Adaptive Immunity, Amino Acid Sequence, Aminopeptidases, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Glycolysis, Immunologic Deficiency Syndromes, Innate Immunity, Lysosomes, Molecular Models, Molecular Sequence Data, Pedigree, Proteolysis, Sequence Alignment, Serine Endopeptidases, Animals, Mice
Source:	Cell
ISSN:	0092-8674
Publisher:	Cell Press
Volume:	159
Number:	7
Page Range:	1578-1590
Date:	18 December 2014
Official Publication:	https://doi.org/10.1016/j.cell.2014.12.001
PubMed:	View item in PubMed

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