Ribonucleic Acid-Mediated Control of Protein Translation Under Stress

Abstract

Significance: The need of cells to constantly respond to endogenous and exogenous stress has necessitated the evolution of pathways to counter the deleterious effects of stress and to restore cellular homeostasis. The inability to activate a timely and adequate response can lead to disease and is a hallmark of aging. Besides protein-coding genes, cells contain a plethora of noncoding regulatory elements that allow cells to respond rapidly and efficiently to external stimuli by activating highly specific and tightly controlled mechanisms. Many of these programs converge on the regulation of translation, one of the most energy-consuming processes in cells. Recent Advances: The noncoding dimension of translational regulation includes short and long noncoding ribonucleic acids (ncRNAs), as well as messenger RNA features, such as the sequence and modification status of the 5' and 3' untranslated regions (UTRs), that do not change the amino acid sequence of the produced protein. Critical Issues: In this review, we discuss the regulatory role of the nonprotein-coding components of translation under stress, particularly oxidative stress. We conclude that the regulation of translation through ncRNAs, UTRs, and nucleotide modifications is emerging as a critical component of the stress response. Future Directions: Further areas of study using long-read sequencing technologies will be discussed. Antioxid. Redox Signal. 39, 374-389.

Keywords: RNA modifications; noncoding RNA; stress; translation.

FIG. 1.

Schematic of the noncoding elements and pathways that regulate translation of mRNAs under stress and that are discussed in this review. All underlined elements are discussed. mRNA, messenger ribonucleic acid.

FIG. 2.

Schematic of rRNA processing. The 18S, 28S, and 5.8S rRNAs are transcribed by Pol I in the nucleolus, a subregion of the nucleus, as a single precursor transcript and extensively processed to their mature forms; 5S rRNA is transcribed separately and imported into the nucleolus. There, ribosomal proteins and mature rRNAs assemble into the ribosomal subunits that are then utilized in translation. ROS can inhibit rRNA transcription and processing resulting in reduced biogenesis and thus reduced translation. Pol I, DNA polymerase I; ROS, reactive oxygen species; rRNA, ribosomal RNA.

FIG. 3.

Overview for generation of stress-induced tRNA fragments (tiRNA). During stress, angiogenin translocates from the nucleus to the cytoplasm and cleaves tRNAs in the anticodon loop. The resulting RNA molecules, termed tiRNAs, can then perform functions that include regulation of translation. tiRNA, tRNA-derived stress-induced RNA; tRNA, transfer RNA.

FIG. 4.

Schematic of circRNA function in cells. CircRNAs can act as sponges for RNA binding proteins and miRNAs and thereby altering the translation of their targets. CircRNAs can also be translated themselves via an IRES that become increasingly utilized for translation initiation during stress-dependent inhibition of cap-dependent translation. circRNA, circular RNA; IRES, internal ribosome entry site; miRNA, micro-RNA.

FIG. 5.

Regulatory pathways of translation that function using mRNA elements in the 5′ UTR. (A) Schematic of the mTORC1 pathway. The activity of the serine/threonine kinase mTORC1 is regulated by cellular growth conditions. When nutrients, energy, and growth factors are in abundance, the mTORC1 complex is activated and promotes translation by phosphorylating S6K, which increases its activity, and by phosphorylating eIF4EBP1, which inhibits its activity. Transcripts with a 5′ TOP motif are more sensitive to eIF4EBP1 and thus mTORC1 activity. (B) Schematic of the ISR. The ISR responds to a diverse array of stressors, including iron deprivation, viral infection, proteotoxic stress, and starvation. A set of four kinases respond to their respective stimuli and a response is integrated into phosphorylation of the translation initiation factor eIF2α, which reduces its affinity for a guanine exchange factor. Without GTP, eIF2α does not participate in translation initiation thereby reducing global translation and increasing ribosome scanning, which leads to the selective translation of the critical ISR transcription factor ATF4. ATF4, activating transcription factor 4; eIF2α, eukaryotic translation initiation factor 2α; GTP, guanosine triphosphate; ISR, integrated stress response; mTORC1, mammalian target of rapamycin complex 1; TOP, terminal oligopyrimidine.

FIG. 6.

Schematic of RNA modifications and their detection by nanopore RNA sequencing. The function of mRNA modifications is, in part, dependent on the region they are located, with consequences ranging from altered mRNA stability to changes in translation efficiency. mRNA modifications can be detected by nanopore RNA sequencing since RNA bases are directly measured through electrical resistance as they are enzymatically forced through the nanopore. In this way, nanopore sequencing sufficiently trained on different mRNA modifications can offer the most authentic view of the epitranscriptome available.