Network analyses reveal pervasive functional regulation between proteases in the human protease web

Area of Science:

• Biochemistry and Molecular Biology
• Systems Biology
• Proteomics

Background:

• Proteolytic processing is a key posttranslational modification influencing biological pathways.
• Proteases were traditionally viewed as acting independently or in isolated cascades.
• Evidence suggests broader, interconnected regulation among proteases and inhibitors.

Purpose of the Study:

• To systematically investigate protease and inhibitor interactions.
• To develop a computational representation of these interactions, termed the protease web.
• To explore the implications of this network for biological regulation.

Main Methods:

• Assembled curated data on protease cleavage and inhibition.
• Developed a global, computational network model (the protease web).
• Analyzed network properties like 'reachability' and tissue-specific subnetworks.

Main Results:

• The protease web demonstrates pervasive influence of proteases on each other and protease inhibitors.
• The network connects diverse protease groups and cascades, challenging the view of isolated action.
• Network predictions, such as MMP8's role in serpinA1 cleavage, were validated in vivo.
• Tissue-specific subnetworks were identified, reflecting distinct cellular phenotypes.

Conclusions:

• Proteases operate within an interconnected network (the protease web), influencing the proteome's functional state.
• This network provides a new dimension for understanding biological control and protease-dependent mechanisms.
• The findings have implications for studying complex biological processes and diseases involving proteases.