Peroxidasin (PXDN) and peroxidasin-like protein (PXDNL) are members of the peroxidase-cyclooxygenase
superfamily. PXDN functions in basement membrane synthesis by forming collagen IV
crosslinks, while the function of PXDNL remains practically unknown. In this work,
we characterized the post-translational proteolytic processing of PXDN and PXDNL.
Using a novel knock-in mouse model, we demonstrate that the proteolytic cleavage of
PXDN occurs in vivo. With the help of furin-specific siRNA we also demonstrate that
the proprotein-convertase, furin participates in the proteolytic processing of PXDN.
Furthermore, we demonstrate that only the proteolytically processed PXDN integrates
into the extracellular matrix, highlighting the importance of the proteolysis step
in PXDN’s collagen IV-crosslinking activity. We also provide multiple lines of evidence
for the importance of peroxidase activity in the proteolytic processing of PXDN. Finally,
we show that PXDNL does not undergo proteolytic processing, despite containing sequence
elements efficiently recognized by proprotein convertases. Collectively, our observations
suggest a previously unknown protein quality control during PXDN synthesis and the
importance of the peroxidase activity of PXDN in this process.
