HTRA1-Dependent Cell Cycle Proteomics

The HTRA1 gene encoding
an evolutionary conserved
protein quality-control factor can be epigenetically silenced or inactivated
by mutation under pathologic conditions such as cancer. Recent evidence
suggests that the loss of HTRA1 function causes multiple phenotypes,
including the acceleration of cell growth, delayed onset of senescence,
centrosome amplification, and polyploidy, suggesting an implication
in the regulation of the cell cycle. To address this model, we performed
a large-scale proteomics study to correlate the abundance of proteins
and HTRA1 levels in various cell cycle phases using label-free-quantification
mass spectrometry. These data indicate that the levels of 4723 proteins
fluctuated in a cell-cycle-dependent manner, 2872 in a HTRA1-dependent
manner, and 1530 in a cell-cycle- and HTRA1-dependent manner. The
large number of proteins affected by the modulation of HTRA1 levels
supports its general role in protein homeostasis. Moreover, the detected
changes in protein abundance, in combination with pull-down data,
implicate HTRA1 in various cell cycle events such as DNA replication,
chromosome segregation, and cell-cycle-dependent apoptosis. These
results highlight the wide implications of HTRA1 in cellular physiology.