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Dual Proteolytic Pathways Govern Glycolysis and Immune Competence

Lookup NU author(s): Dr David McDonald, Dr Bernadette Carroll, Nicholas Robertson, Dr Helen GriffinORCiD, Professor Jeremy LakeyORCiD, Dr Louise Reynard, Professor Andrew Cant, Dr Viktor Korolchuk, Professor Sophie HambletonORCiD


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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-gamma and IL-1 beta. 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.

Publication metadata

Author(s): Lu W, Zhang Y, McDonald DO, Jing HE, Carroll B, Robertson N, Zhang Q, Griffin H, Sanderson S, Lakey JH, Morgan NV, Reynard LN, Zheng L, Murdock HM, Turvey SE, Hackett SJ, Prestidge T, Hall JM, Cant AJ, Matthews HF, Koref MFS, Simon AK, Korolchuk VI, Lenardo MJ, Hambleton S, Su HC

Publication type: Article

Publication status: Published

Journal: Cell

Year: 2014

Volume: 159

Issue: 7

Pages: 1578-1590

Online publication date: 18/12/2014

Acceptance date: 30/11/2014

ISSN (print): 0092-8674

ISSN (electronic): 1097-4172

Publisher: Cell Press


DOI: 10.1016/j.cell.2014.12.001


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Funder referenceFunder name
Newcastle upon Tyne Hospitals NHS Charity
NIHR Newcastle Biomedical Research Centre
NIHR Oxford Biomedical Research Centre
Intramural Research Program of the NIAID, NIH
Sir Jules Thorn Charitable Trust
MOP-133691Canadian Institutes of Health Research