Dual proteolytic pathways govern glycolysis and immune competence PMID: 25525876

ADC Targets in Oncology

2026-04-10

Dual proteolytic pathways govern glycolysis and immune competence

Cell. 2014 Dec 18;159(7):1578-90. doi: 10.1016/j.cell.2014.12.001.

Wei Lu ¹ , Yu Zhang ² , David O McDonald ³ , Huie Jing ² , Bernadette Carroll ⁴ , Nic Robertson ⁵ , Qian Zhang ² , Helen Griffin ⁶ , Sharon Sanderson ⁷ , Jeremy H Lakey ⁴ , Neil V Morgan ⁸ , Louise N Reynard ³ , Lixin Zheng ¹ , Heardley M Murdock ⁹ , Stuart E Turvey ¹⁰ , Scott J Hackett ¹¹ , Tim Prestidge ¹² , Julie M Hall ¹³ , Andrew J Cant ⁵ , Helen F Matthews ¹ , Mauro F Santibanez Koref ⁶ , Anna Katharina Simon ¹⁴ , Viktor I Korolchuk ⁴ , Michael J Lenardo ¹ , Sophie Hambleton ¹⁵ , Helen C Su ¹⁶

Affiliations

1. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; NIAID Clinical Genomics Program, National Institutes of Health, Bethesda, MD 20892, USA.
2. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; NIAID Clinical Genomics Program, National Institutes of Health, Bethesda, MD 20892, USA.
3. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
4. Institute of Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
5. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK.
6. Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
7. NIHR BRC Translational Immunology Lab, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
8. Centre for Cardiovascular Sciences, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
9. NIAID Clinical Genomics Program, National Institutes of Health, Bethesda, MD 20892, USA; Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
10. Department of Pediatrics, Child & Family Research Institute and BC Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
11. Paediatric Immunology Department, Birmingham Heartlands Hospital, Birmingham B9 5SS, UK.
12. Blood and Cancer Center, Starship Children's Hospital, Auckland 1142, New Zealand.
13. Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK.
14. NIHR BRC Translational Immunology Lab, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK; MRC Unit Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
15. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK. Electronic address: [email protected].
16. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; NIAID Clinical Genomics Program, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: [email protected].

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.