Posttranslational processing and modification of cathepsins and cystatins

Area of Science:

• Biochemistry
• Cell Biology

Background:

• Cathepsins are essential proteases regulating protein catabolism and synthesis.
• Post-translational modifications are crucial for cathepsin targeting and activity regulation.

Purpose of the Study:

• To elucidate the intricate post-translational processing and modification pathways of cathepsins.
• To understand the role of cystatins, specifically cystatin α, as endogenous cathepsin inhibitors.

Main Methods:

• Analysis of cathepsin synthesis from pre-pro-mature forms.
• Investigation of lysosomal targeting via mannose-6-phosphate signaling.
• Examination of cystatin α phosphorylation, conjugation, and redox-dependent inactivation.

Main Results:

• Cathepsins undergo cotranslational pre-peptide removal, Golgi processing, glycosylation, and lysosomal targeting.
• Degradation involves limited proteolysis, ubiquitination, and proteasomal processing into amino acids.
• Cystatin α in skin is phosphorylated, conjugated to filaggrin, and inactivated by glutathione or dimerization, regulated by redox potential.

Conclusions:

• Cathepsin function is tightly regulated through complex post-translational modifications and inhibitory mechanisms.
• Cystatin α plays a unique role in skin structure, with its activity modulated by cellular redox state.