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Coordination of protein synthesis and decay in mammalian cells

ABSTRACT: Protein synthesis and decay rates must be tightly coordinated to ensure proteome homeostasis. How this coordination is established is unknown. Here we use quantitative live cell imaging combined with computational inference and proteomics to determine how changes in global protein synthesis rates alter protein decay rates. A passive adaptation of protein degradation and dilution rates operates in cells tightly coupling proliferation rate to protein synthesis rates, allowing to partially buffer changes in proteome concentrations with increased loss of short-lived proteins. In contrast, the proliferation rate of mouse embryonic stem cells (mESCs) is hyposensitive to moderate changes in protein synthesis. mESCs uncouple protein degradation and dilution rates and robustly maintain their protein levels. Finally, we also show that differentiated human astrocytes strongly adapt protein degradation rates to altered protein synthesis. Our work illuminates the complex interplay between protein synthesis, degradation, and cell division to regulate proteome homeostasis.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Fibroblast, Embryonic Stem Cell

SUBMITTER: Benjamin Martin

LAB HEAD: David Michael Suter

PROVIDER: PXD056601 | Pride | 2025-10-07

REPOSITORIES: Pride

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			Action	DRS
	BM_231114_1241_Expl_01.raw	Raw
	BM_231114_1241_Expl_02.raw	Raw
	BM_231114_1241_Expl_03.raw	Raw
	BM_231114_1241_Expl_04.raw	Raw
	BM_231114_1241_Expl_05.raw	Raw

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Project description:Steady-state RNA levels are a result of RNA synthesis and degradation. The importance of transcription-factor mediated induction or repression of mRNA synthesis is well established, but the role and mechanisms of RNA degradation are less well understood. We globally evaluated the RNA decay rates in proliferating and differentiated mouse myoblasts on whole-genome Affymetrix exon arrays, allowing for the assessment of directionality of RNA degradation and the detection of splice variant-specific differences in RNA decay rates. We found large differences in decay rates. mRNAs coding for proteins involved in signal transduction and transcriptional regulation have shortest half lives, whereas mRNAs coding for DNA replication enzymes and muscle contraction proteins are among the most stable. Many genes differentially expressed between proliferating and differentiated myoblasts demonstrate major differences in RNA decay rates. Quantitative PCR experiments confirmed the higher stability of transcripts with increased expression levels. RNA degradation has no apparent preferential directionality. RNA degradation appears to affect the ratio of different splice variants. For example, Itga7 isoforms with higher abundance in differentiated than in proliferating cells are more stable in differentiated cells, despite the sharing of a common 3’ untranslated region. Thus, where it was previously thought that the abundance of different splice isoforms was mainly controlled by tissue-specific splicing factors, we now demonstrate that isoforms may be produced at comparable levels but degraded with different efficiencies, depending on the differentiation status of the cells. Our results indicate that control of RNA degradation rates contributes significantly to the differentiation stage-dependent differences in abundance of transcripts and splice variants. Keywords: total RNA expression profiling; cultured cells We analyzed proliferating C2C12 cells and C2C12 cells differentiated into myotubes by serum starvation (8 days after induction of differentiation). We analyzed 7 time points after addition of actionmycin D (0, 10, 20, 30, 60, 150, 480 minutes). There were two biological replicates per condition.

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Coordination of protein synthesis and decay in mammalian cells

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