Dual proteolytic pathways govern glycolysis and immune competence.

Item Type:	Article
Title:	Dual proteolytic pathways govern glycolysis and immune competence.
Creators Name:	Lu, W. and Zhang, Y. and McDonald, D.O. and Jing, H. and Carroll, B. and Robertson, N. and Zhang, Q. and Griffin, H. and Sanderson, S. and Lakey, J.H. and Morgan, N.V. and Reynard, L.N. and Zheng, L. and Murdock, H.M. and Turvey, S.E. and Hackett, S.J. and Prestidge, T. and Hall, J.M. and Cant, A.J. and Matthews, H.F. and Koref, M.F.S. and Simon, A.K. and Korolchuk, V.I. and Lenardo, M.J. and 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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