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Abstract
Proteins are continuously synthesized during cell growth and proliferation. At the same time, excessive and misfolded proteins have to be degraded, otherwise they are a burden to cells. Protein degradation is essential to maintain proteostasis in cells, and dysfunction of protein degradation systems results in numerous diseases such as cancer and neurodegenerative diseases. Despite the importance of protein degradation, the degradation pathways of many proteins remain to be explored. Here, we comprehensively investigated the degradation of newly synthesized proteins in human cells by integrating metabolic labeling, click chemistry, and multiplexed proteomics, and systematic and quantitative analysis of newly synthesized proteins first revealed the degradation pathways of many proteins. Bioinformatic analysis demonstrates that proteins degraded through two major pathways have distinct properties and functions. Proteins degraded through the ubiquitin-proteasome pathway contain more disordered structures, whereas those through the autophagy-lysosome pathway have significantly higher hydrophobicity. Systematic and quantitative investigation of the dynamics of newly synthesized proteins provides unprecedented and valuable information about protein degradation, which leads to a better understanding of protein properties and cellular activities.
Highlights
The maintenance of proteostasis is vital for cell survival, growth, and division.[1,2] Protein degradation is responsible for the removal of unnecessary proteins, such as misfolded and excessive proteins, and is essential to maintain protein homeostasis
We integrated metabolic labeling, click chemistry and mass spectrometry (MS)-based proteomics to systematically study the dynamics of newly synthesized proteins and their degradation pathways
Through the integration of metabolic labeling, click chemistry and MS-based proteomics, we systematically investigated the dynamics of newly synthesized proteins in MCF-7 cells and measured their half-lives
Summary
The maintenance of proteostasis is vital for cell survival, growth, and division.[1,2] Protein degradation is responsible for the removal of unnecessary proteins, such as misfolded and excessive proteins, and is essential to maintain protein homeostasis. There are two major types of protein degradation pathways, i.e. the ubiquitin-proteasome and the autophagy-lysosome pathways. Proteins are ubiquitinated by ubiquitin ligase complexes and degraded by the proteasome,[3] while in the autophagy-lysosomal pathway, proteins and organelles are captured in the autophagosome and further degraded by proteases in the lysosome.[4] Dysfunctional protein degradation pathways result in numerous diseases, including cancer, neurodegenerative disorders, and cardiovascular diseases.[5,6] Systematic investigation of protein degradation and dynamics will help us gain a better understanding of protein degradation pathways, and identify the underlying mechanisms of protein degradation
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