TUSK: a ubiquitin hydrolase complex modulating surface protein abundance in trypanosomes

Area of Science:

• Cellular Biology
• Parasitology
• Protein Regulation

Background:

• Protein homeostasis is essential for cellular function and adaptation.
• In African trypanosomes, surface proteins are critical for immune evasion, drug sensitivity, and environmental sensing.
• Deubiquitinase orthologs like Usp7 and Vdu1 influence the abundance of trypanosome surface proteins.

Purpose of the Study:

• To identify and characterize novel regulators of trypanosome surface protein levels.
• To elucidate the function of Skp1 paralogs, specifically SkpZ, in protein abundance control.
• To understand the coordination between trans-membrane and GPI-anchored surface proteins.

Main Methods:

• Identification of Skp1 paralogs in trypanosomes.
• Affinity isolation and Liquid Chromatography-Mass Spectrometry (LC-MS/MS) to identify protein complexes.
• Gene silencing (knockdown) to assess the functional impact of SkpZ.

Main Results:

• A divergent Skp1 paralog, SkpZ, was identified and shown to form a heterotrimeric complex with TbUsp7 and TbTpr86 (the TUSK complex).
• Silencing SkpZ led to decreased abundance of TbUsp7 and TbTpr86, confirming their direct association.
• SkpZ knockdown resulted in decreased levels of trans-membrane domain (TMD) proteins and increased levels of GPI-anchored surface proteins.

Conclusions:

• The TUSK complex (TbTpr86, TbUsp7, SkpZ) is a novel regulator of trypanosome surface protein expression.
• This complex plays a key role in coordinating the expression levels of TMD and GPI-anchored proteins.
• The TUSK complex offers a potential target for modulating trypanosome surface protein dynamics.