FAP finds FGF21 easy to digest

Area of Science:

• Endocrinology
• Metabolism
• Protease biochemistry

Background:

• Fibroblast growth factor 21 (FGF21) is a key metabolic regulator.
• Circulating FGF21 is inactivated in humans via C-terminal proteolytic cleavage.
• The specific enzyme and mechanism for FGF21 inactivation were previously unknown.

Purpose of the Study:

• To identify the endopeptidase responsible for human FGF21 (hFGF21) inactivation.
• To elucidate the post-translational regulation of FGF21 activity.
• To explore potential therapeutic strategies targeting FGF21 inactivation.

Main Methods:

• Biochemical assays to identify protease activity against hFGF21.
• Site-specific cleavage analysis of hFGF21.
• Enzyme kinetics studies.

Main Results:

• Fibroblast activation protein (FAP) was identified as the endopeptidase cleaving hFGF21.
• FAP mediates site-specific cleavage at the C-terminus of hFGF21.
• This cleavage inactivates FGF21 signaling.

Conclusions:

• Fibroblast activation protein (FAP) is the primary enzyme responsible for inactivating human FGF21.
• Inhibiting FAP may represent a therapeutic approach to enhance endogenous active FGF21 levels.
• Understanding this mechanism provides insights into metabolic regulation and potential therapeutic interventions.