Reprogramming mRNA translation during stress

Abstract

The survival of mammalian cells exposed to adverse environmental conditions requires a radical reprogramming of protein translation. Stress-activated kinases target components of the initiation machinery (e.g. eIF2alpha, eIF4E-BP, eIF4B, and ribosomal protein S6) to inhibit the translation of 'housekeeping' proteins and promote the translation of repair enzymes. Accumulating untranslated mRNA is concentrated at stress granules where it is sorted and triaged to sites of storage, reinitiation, or decay. At the same time, the translation of mRNAs encoding repair enzymes is selectively preserved by both internal ribosome entry site-dependent and -independent mechanisms. In combination, these stress-activated processes coordinately reprogram mRNA translation and decay in a way that conserves anabolic energy, preserves essential mRNAs, and promotes the repair of stress-induced molecular damage.

Figure 1

General translation inhibition by stress. (A) Phosphorylation of eIF2α (P-eIF2α) is induced by GCN2 (amino acid starvation, UV), PKR (dsRNA), HRI (low heme, arsenite, osmotic stress, heat stress) or PERK (ER stress). P-eIF2α blocks translation initiation by inhibiting the eIF2/GTP/tRNA^Met ternary complex. (B) Energy starvation elevates the AMP/ATP ratio activating the AMPK-TSC pathway. This in turn attenuates mTORC1 activity to inhibit phosphorylation of 4E-BP and S6K. (C) 28S rRNA cleaved by IREβ. The resulting structural alteration inhibits translation by an unknown mechanism. (D) Hyper-edited inosine containing dsRNA (I-dsRNA) is produced by ADAR1 whose protein expression is up-regulated by serum starvation. I-dsRNA inhibits translation at initiation probably by nucleating the assembly of stress granules (SGs). The localization of ADAR1 in SGs has not been confirmed, however, APOBEC3G, a C to U RNA editing enzyme, is found in SGs. indicates the possible SG-related mechanism.

Figure 2

Transcript specific translation inhibition by stress. (A) In stressed cells, some transcription factors (e.g. p53, HIF1α) promote the expression of miRNAs that reduce the translation of selected targeted mRNAs. (B) Stress induces the expression of RNA editing enzymes to alter the processing of primary miRNA transcripts. Moreover, editing of pre-miRNA, can alter its target specificity. (C) SGs may regulate miRNA function by sequestering argonaute, miRNAs and RNA editing enzymes. It is possible that miRNPs are sorted, modified, and delivered to target mRNAs at the SG.