Elucidating Proteoform Dynamics Underlying the Senescence Associated Secretory Phenotype
Peter F Doubleday1, Luca Fornelli2, Neil L Kelleher1
1Department of Molecular Biosciences, Proteomics Center of Excellence , Northwestern University , Evanston , Illinois 60208 , United States.
Journal of Proteome Research
|January 16, 2020
Summary
Cellular senescence, a tumor-suppressive process, involves proteomic changes and a detrimental secretome. This study reveals proteoform complexity in secreted proteins, offering insights into senescence dynamics.
Area of Science:
- Cell Biology
- Proteomics
- Molecular Biology
Background:
- Cellular senescence is a key tumor-suppressive mechanism and a factor in organismal aging.
- Temporal dynamics of senescence remain understudied.
- Previous secretome analyses lack proteoform-level detail.
Purpose of the Study:
- To investigate temporal proteomic changes during senescence.
- To define the molecular complexity of secreted proteins using top-down proteomics.
- To elucidate isoform-specific modifications and cleavage in the senescence secretome.
Main Methods:
- Quantitative proteomics (global intracellular and top-down).
- Forced HRASG12V expression to induce senescence in diploid fibroblasts.
- Analysis of secreted proteins <30 kDa.
Main Results:
- Intracellular proteomic changes correlate with senescence-associated secretory phenotype and cell cycle exit.
- The senescence secretome, while reinforcing cell cycle exit, can harm tissue homeostasis.
- Identified distinct proteoforms of immune regulators (e.g., interleukin-8) and temporally resolved their dynamics.
Conclusions:
- Senescence involves complex intracellular and secreted proteomic shifts.
- Top-down proteomics reveals significant proteoform complexity in secreted proteins.
- Understanding proteoform dynamics is crucial for senescence research and its implications in aging and cancer.
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