Human HtrA1 (high-temperature requirement
protein A1) belongs to
a conserved family of serine proteases involved in protein quality
control and cell fate. The homotrimeric ubiquitously expressed protease
has chymotrypsin-like specificity and primarily targets hydrophobic
stretches in selected or misfolded substrate proteins. In addition,
the enzyme is capable of exerting autolytic activity by removing the
N-terminal insulin-like growth factor binding protein (IGFBP)/Kazal-like
tandem motif without affecting the protease activity. In this study,
we have addressed the mechanism governing the autolytic activity and
find that it depends on the integrity of the disulfide bonds in the
N-terminal IGFBP/Kazal-like domain. The specificity of the autolytic
cleavage reveals a strong preference for cysteine in the P1 position
of HtrA1, explaining the lack of autolysis prior to disulfide reduction.
Significantly, the disulfides were reduced by thioredoxin, suggesting
that autolysis of HtrA1 in vivo is linked to the
endogenous redox balance and that the N-terminal domain acts as a
redox-sensing switch.