Dual proteolytic pathways govern glycolysis and immune competence

Wei Lu, Yu Zhang, David O. McDonald, Huie Jing, Bernadette Carroll, Nic Robertson, Qian Zhang, Helen Griffin, Sharon Sanderson, Jeremy H. Lakey, Neil V. Morgan, Louise N. Reynard, Lixin Zheng, Heardley M. Murdock, Stuart E. Turvey, Scott J. Hackett, Tim Prestidge, Julie M. Hall, Andrew J. Cant, Helen F. MatthewsMauro F Santibanez Koref, Anna Katharina Simon, Viktor I. Korolchuk, Michael J. Lenardo, Sophie Hambleton, Helen C. Su

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28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1578-1590
Number of pages13
JournalCell
Volume159
Issue number7
DOIs
Publication statusPublished - 18 Dec 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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., ... Su, H. C. (2014). Dual proteolytic pathways govern glycolysis and immune competence. Cell, 159(7), 1578-1590. https://doi.org/10.1016/j.cell.2014.12.001