Dual proteolytic pathways govern glycolysis and immune competence

Area of Science:

• Cellular Biology
• Immunology
• Neuroscience

Background:

• Proteasomes and lysosomes are key cellular systems for protein catabolism and amino acid recycling.
• Tripeptidyl peptidase II (TPPII) is a cytosolic proteolytic complex that works with the proteasome-ubiquitin pathway.
• Autosomal recessive TPP2 mutations are linked to human conditions including infections, autoimmunity, and neurodevelopmental delay.

Purpose of the Study:

• To investigate the function of TPPII in mammalian cells.
• To elucidate the molecular mechanisms underlying TPP2-related disorders.
• To understand the role of TPPII in cellular metabolism, immunity, and neurodevelopment.

Main Methods:

• Analysis of TPPII-deficient cells.
• Investigation of cellular compensation mechanisms, including lysosome activity and autophagy.
• Measurement of amino acid levels, glycolysis, and cytokine production (IFN-γ, IL-1β).

Main Results:

• TPPII deficiency leads to increased lysosome number and proteolytic activity as a compensatory mechanism.
• Overabundant lysosomes degrade hexokinase-2 via chaperone-mediated autophagy, disrupting glycolysis.
• Impaired glycolysis reduces effector cytokine production, impacting immune responses.

Conclusions:

• TPPII plays a critical role in maintaining intracellular amino acid homeostasis.
• TPPII regulates the balance between lysosome activity and glycolysis.
• Dysregulation of TPPII impacts innate and adaptive immunity and neurodevelopmental health.