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.

中文翻译：

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HTRA1依赖性细胞周期蛋白质组学

该HTRA1编码进化保守蛋白质量控制因子的基因可以在诸如癌症的病理条件下通过表观遗传沉默或失活。最近的证据表明，HTRA1功能的丧失会导致多种表型，包括细胞生长的加速，衰老的发作延迟，中心体扩增和多倍性，这暗示着细胞周期调控的意义。为了解决该模型，我们进行了大规模蛋白质组学研究，使用无标记定量质谱法将各种细胞周期阶段的蛋白质丰度与HTRA1水平相关联。这些数据表明4723蛋白的水平以细胞周期依赖性方式波动，2872以HTRA1依赖性方式波动，1530以细胞周期和HTRA1依赖性方式波动。受HTRA1水平调节影响的大量蛋白质支持其在蛋白质稳态中的一般作用。此外，检测到的蛋白质丰度变化与下拉数据相结合，意味着HTRA1参与了各种细胞周期事件，例如DNA复制，染色体分离和细胞周期依赖性凋亡。这些结果突出了HTRA1在细胞生理学中的广泛意义。