Dual proteolytic pathways govern glycolysis and immune competence.

Lu, Wei, Zhang, Yu, McDonald, David O, Jing, Huie, Carroll, Bernadette, Robertson, Nic, Zhang, Qian, Griffin, Helen, Sanderson, Sharon, Lakey, Jeremy H, Morgan, Neil V, Reynard, Louise N, Zheng, Lixin, Murdock, Heardley M, Turvey, Stuart E, Hackett, Scott J, Prestidge, Tim, Hall, Julie M, Cant, Andrew J, Matthews, Helen F, Koref, Mauro F Santibanez, Simon, Anna Katharina, Korolchuk, Viktor I, Lenardo, Michael J, Hambleton, Sophie and Su, Helen C (2014) Dual proteolytic pathways govern glycolysis and immune competence. Cell, 159 (7). pp. 1578-90. ISSN 1097-4172. This article is accessible to all HEFT staff and students via NICE journals and databases http://www.nice.org.uk/about/what-we-do/evidence-services/journals-and-databases by using their HEFT Athens login IDs

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Official URL: http://www.cell.com/cell/fulltext/S0092-8674(14)01...

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.

Item Type: Article
Additional Information: This article is accessible to all HEFT staff and students via NICE journals and databases http://www.nice.org.uk/about/what-we-do/evidence-services/journals-and-databases by using their HEFT Athens login IDs
Subjects: WS Paediatrics. Child health
Divisions: Womens and Childrens > Paediatrics
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Depositing User: Mrs Caroline Tranter
Date Deposited: 31 May 2015 07:25
Last Modified: 31 May 2015 07:25
URI: http://www.repository.uhblibrary.co.uk/id/eprint/945

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