title: Dual proteolytic pathways govern glycolysis and immune competence.
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.
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: David O
authors.initials: DO
authors.lastname: McDonald
authors.affiliation: 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.
authors.forename: Huie
authors.initials: H
authors.lastname: Jing
authors.affiliation: Institute of Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Carroll
authors.affiliation: 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.
authors.forename: Nic
authors.initials: N
authors.lastname: Robertson
authors.affiliation: 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.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Griffin
authors.affiliation: NIHR BRC Translational Immunology Lab, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: Sanderson
authors.affiliation: Institute of Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Lakey
authors.affiliation: Centre for Cardiovascular Sciences, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Neil V
authors.initials: NV
authors.lastname: Morgan
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Louise N
authors.initials: LN
authors.lastname: Reynard
authors.affiliation: 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.
authors.forename: Lixin
authors.initials: L
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Heardley M
authors.initials: HM
authors.lastname: Murdock
authors.affiliation: Department of Pediatrics, Child & Family Research Institute and BC Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Turvey
authors.affiliation: Paediatric Immunology Department, Birmingham Heartlands Hospital, Birmingham B9 5SS, UK.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hackett
authors.affiliation: Blood and Cancer Center, Starship Children's Hospital, Auckland 1142, New Zealand.
authors.forename: Tim
authors.initials: T
authors.lastname: Prestidge
authors.affiliation: Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Hall
authors.affiliation: 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.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Cant
authors.affiliation: 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.
authors.forename: Helen F
authors.initials: HF
authors.lastname: Matthews
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Mauro F Santibanez
authors.initials: MF
authors.lastname: Koref
authors.affiliation: 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.
authors.forename: Anna Katharina
authors.initials: AK
authors.lastname: Simon
authors.affiliation: Institute of Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Viktor I
authors.initials: VI
authors.lastname: Korolchuk
authors.affiliation: 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.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
authors.affiliation: 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: sophie.hambleton@newcastle.ac.uk.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hambleton
authors.affiliation: 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: hsu@niaid.nih.gov.
authors.forename: Helen C
authors.initials: HC
authors.lastname: Su
mesh_terms: D056704:Adaptive Immunity; D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006019:Glycolysis; D006801:Humans; D007113:Immunity, Innate; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010375:Pedigree; D059748:Proteolysis; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases