Transcriptome analysis reveals the differences between cellular response to ribosomal stress and translational stress

Abstract

Ribosome biogenesis is an essential metabolic process of a growing cell. Cells need to continuously synthesize new ribosomes in order to make new proteins than can support building biomass and cell division. It is obvious that in the absence of ribosome biogenesis, cell growth will stop and cell division will stall. However, it is not clear whether cell growth stops due to reduced protein synthesis capacity (translational stress) or due to activation of signaling specific to ribosome biogenesis abnormalities (ribosomal stress). To understand the signaling pathways leading to cell cycle arrest under ribosomal and translational stress conditions, we performed time series RNA-seq experiments of cells at different time of ribosomal and translational stress. We found that expression of ribosomal protein genes follow different course over the time of these two stress types. In addition, ribosomal stress is sensed early in the cell, as early as 2hr. Up-regulation of genes responsive to oxidative stress and over representation of mRNAs for transcription factors responsive to stress was detected in cell at 2hr of ribosomal protein depletion. Even though, we detected phenotypic similarities in terms of cell separation and accumulation in G1 phase cells during inhibition of ribosome formation and ribosome function, different gene expression patterns underlie these phenotypes, indicating a difference in causalities of these phenotypes. Both ribosomal and translational stress show common increased expression of stress responsive gene expression, like Crz1 target gene expression, signature of oxidative stress response and finally membrane or cell wall instability. We speculate that cell membrane and cell wall acts as major stress sensor in the cell and adjust cellular metabolism accordingly. Any change in membrane lipid composition, or membrane protein oxidation, or decrease or increase in intracellular turgor pressure causes stress in cell membrane. Cell membrane or cell wall stress activates and/or inactivates specific signaling pathway which triggers stress responsive gene expression and adaptation of cellular behavior accordingly.