Translational Control under Stress: Reshaping the Translatome

Abstract

Adequate reprogramming of cellular metabolism in response to stresses or suboptimal growth conditions involves a myriad of coordinated changes that serve to promote cell survival. As protein synthesis is an energetically expensive process, its regulation under stress is of critical importance. Reprogramming of messenger RNA (mRNA) translation involves well-understood stress-activated kinases that target components of translation initiation machinery, resulting in the robust inhibition of general translation and promotion of the translation of stress-responsive proteins. Translational arrest of mRNAs also results in the accumulation of transcripts in cytoplasmic foci called stress granules. Recent studies focus on the key roles of transfer RNA (tRNA) in stress-induced translational reprogramming. These include stress-specific regulation of tRNA pools, codon-biased translation influenced by tRNA modifications, tRNA miscoding, and tRNA cleavage. In combination, signal transduction pathways and tRNA metabolism changes regulate translation during stress, resulting in adaptation and cell survival. This review examines molecular mechanisms that regulate protein synthesis in response to stress.

Keywords: stress; tRNA; translation; translation initiation; translational reprogramming.

Figure 1.

A. The translation initiation ternary complex (TC) consisting of eIF2-GTP-Met-tRNA_i is a part of 43S pre-initiation complex (PIC) required for cap-dependent translation initiation. Decoding of AUG ‘start’ codon at P-site leads to GTP hydrolysis and releases of eIF2-GDP. Phosphorylation of eIF2 at Ser-51 of the α-subunit by stress induced kinases GCN2 (UV and amino acid starvation), HRI (heme deficiency, oxidative stress and heat shock), PERK (hypoxia, ER stress and proteostasis) and PKR (viral infection and dsRNA) prevents GDP to GTP exchange by nucleotide exchange factor eIF2B, the step required to regenerate the TC. This stress-mediated eIF2α phosphorylation results in global cap-dependent translational inhibition, stimulates stress granule (SG) assembly and promotes selective translation of stress-responsive mRNAs. B. mTORC1 is a positive regulator of cap-dependent translation. Increased activity of mTORC1 results in the phosphorylation of translational repressor eIF4E-binding proteins (4E-BPs) and ribosomal S6 kinases (S6K½). These phosphorylation events are proposed to regulate translation of TOP/TOP like mRNAs. Treatment with mTOR inhibitors (e.g., rapamycin or Torin) or starvation conditions decreases the activity of mTORC1, thus inhibiting global translation and promoting stress responses.

Figure 2.

MAF1 is a negative regulator of Pol III-mediated transcription of tRNA genes. Under normal growth conditions, mTORC1 mediated phosphorylation of MAF1 prevents its binding to with Pol III. This ensures optimal transcription of tRNA genes to meet cellular metabolic needs. Decreased activity of mTORC1 under conditions of stress leads to decreased phosphorylation of MAF1 thereby promoting its association with Pol III. This results in differential transcription of tRNA genes that alters the cellular tRNA pool to favor translation of stress-responsive proteins.

Figure 3.

Stress alters tRNA metabolism to dynamically reprogram translation to achieve pro-survival equilibrium until optimal conditions are reached. Selective methylation of nucleotide bases in the anti-codon loop by Transfer RNA methyltransferases (Trms) under conditions of oxidative and xenobiotic stress helps maintain translational fidelity and promote codon biased translation of specific transcripts called Modification Tunable Transcripts (MoTTs). Nutrient starvation and ROS conditions promote misacylation of tRNAs that increase decoding of near-cognate tRNAs leading to increased synthesis of stress responsive proteins. Further, stress-mediated cleavage of tRNAs by RNases like angiogenin (ANG) generates tRNA halves (5` and 3` tiRNAs) that facilitate cell viability. Mechanistically, tiRNA interact with translation machinery components and inhibit mRNA translation in eIF2α-independent manner. tRNA fragments smaller that tiRNAs called tRFs, which mimic miRNAs in size, are speculated to regulate protein synthesis in RNAi like/sequence specific manner.