Centre of Medical Biotechnology, Faculty of Biology , University Duisburg-Essen, Universitaetsstrasse , 45141 Essen , Germany.
School of Biosciences , Cardiff University , Cardiff CF10 3US , United Kingdom.
J Proteome Res. 2018 Aug 3;17(8):2679-2694. doi: 10.1021/acs.jproteome.8b00129. Epub 2018 Jul 13.
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.
HTRA1 基因编码一种进化上保守的蛋白质质量控制因子，在癌症等病理条件下可以通过表观遗传沉默或突变失活。最近的证据表明，HTRA1 功能的丧失会导致多种表型，包括细胞生长加速、衰老延迟、中心体扩增和多倍体，表明其在细胞周期调控中的作用。为了验证这一模型，我们使用无标记定量质谱法进行了大规模蛋白质组学研究，以关联不同细胞周期阶段的蛋白质丰度和 HTRA1 水平。这些数据表明，4723 种蛋白质的水平呈细胞周期依赖性波动，2872 种蛋白质的水平呈 HTRA1 依赖性波动，1530 种蛋白质的水平呈细胞周期和 HTRA1 依赖性波动。HTRA1 水平调节所影响的大量蛋白质支持其在蛋白质稳态中的普遍作用。此外，检测到的蛋白质丰度变化，结合下拉数据，表明 HTRA1 参与了各种细胞周期事件，如 DNA 复制、染色体分离和细胞周期依赖性细胞凋亡。这些结果突出了 HTRA1 在细胞生理学中的广泛影响。
