Systematic analysis of protein stability associated with species-specific developmental tempo

Abstract

AbstractHuman embryonic development is generally slower compared with mouse, and one of the model systems for such inter-species differences in developmental tempo is the segmentation clock. The oscillation period of the human segmentation clock, as measured in induced presomitic mesoderm (iPSM) cells, is two times longer than that of mouse. While the core clock gene HES7 is known to show slower protein degradation in human iPSM compared with mouse iPSM, it remains unclear whether the concept of species-specific protein stability is generalizable to other genes. Here we systematically compared the protein degradation rates of approximately 5000 genes between human and mouse iPSM by using dynamic SILAC-based proteomics, demonstrating a pervasive trend of slower protein degradation in human cells. The inter-species difference was observed not only for proteasome-mediated but also for lysosome-mediated degradation. We further investigated the effect of metabolism on the protein stability profile. Treating mouse iPSM cells with a glycolysis inhibitor extended the segmentation clock period, aligning the protein stability profile more closely with that of human cells, though with less effect on lysosome-mediated degradation. These results highlight the universality of slower protein degradation in human development compared with mouse, and suggest metabolism as one of the modulators.