Proteome-wide modulation of degradation dynamics in response to growth arrest

Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):E10329-E10338. doi: 10.1073/pnas.1710238114. Epub 2017 Nov 13.

Abstract

In dividing cells, cytoplasmic dilution is the dominant route of clearance for long-lived proteins whose inherent degradation is slower than the cellular growth rate. Thus, as cells transition from a dividing to a nondividing state, there is a propensity for long-lived proteins to become stabilized relative to short-lived proteins, leading to alterations in the abundance distribution of the proteome. However, it is not known if cells mount a compensatory response to counter this potentially deleterious proteostatic disruption. We used a proteomic approach to demonstrate that fibroblasts selectively increase degradation rates of long-lived proteins as they transition from a proliferating to a quiescent state. The selective degradation of long-lived proteins occurs by the concurrent activation of lysosomal biogenesis and up-regulation of macroautophagy. Through this mechanism, quiescent cells avoid the accumulation of aged long-lived proteins that would otherwise result from the absence of cytoplasmic dilution by cell division.

Keywords: lysosome; protein degradation; protein homeostasis; quantitative proteomics; quiescence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Autophagy / genetics*
  • Autophagy-Related Protein 5 / deficiency
  • Autophagy-Related Protein 5 / genetics
  • Cathepsins / genetics
  • Cathepsins / metabolism
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Checkpoints / genetics
  • Cycloheximide / pharmacology
  • Cytokinesis / drug effects
  • Cytokinesis / genetics
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Gene Expression Regulation
  • Gene Ontology
  • Half-Life
  • Homeostasis / genetics*
  • Humans
  • Kinetics
  • Lysosomes / metabolism*
  • Molecular Sequence Annotation
  • Muscle Proteins / antagonists & inhibitors
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Primary Cell Culture
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteolysis
  • Proteome / genetics
  • Proteome / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • ATG5 protein, human
  • Autophagy-Related Protein 5
  • Muscle Proteins
  • PSME1 protein, human
  • Proteome
  • RNA, Small Interfering
  • Cycloheximide
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Cathepsins
  • Proteasome Endopeptidase Complex