An mRNA-specific tRNA_icarrier eIF2A plays a pivotal role in cell proliferation under stress conditions: stress-resistant translation of c-Src mRNA is mediated by eIF2A

Abstract

c-Src, a non-receptor protein tyrosine kinase, activates NF-κB and STAT3, which in turn triggers the transcription of anti-apoptosis- and cell cycle-related genes. c-Src protein regulates cell proliferation, cell motility and programmed cell death. And the elevated level of activated c-Src protein is related with solid tumor generation. Translation of c-Src mRNA is directed by an IRES element which mediates persistent translation under stress conditions when translation of most mRNAs is inhibited by a phosphorylation of the alpha subunit of eIF2 carrying the initiator tRNA (tRNAi) to 40S ribosomal subunit under normal conditions. The molecular basis of the stress-resistant translation of c-Src mRNA remained to be elucidated. Here, we report that eIF2A, an alternative tRNAi carrier, is responsible for the stress-resistant translation of c-Src mRNA. eIF2A facilitates tRNAi loading onto the 40S ribosomal subunit in a c-Src mRNA-dependent manner. And a direct interaction between eIF2A and a stem-loop structure (SL I) in the c-Src IRES is required for the c-Src IRES-dependent translation under stress conditions but not under normal conditions. Finally, we showed that the eIF2A-dependent translation of c-Src mRNA plays a pivotal role in cell proliferation under stress conditions.

Repeat‐associated non‐ AUG translation in C9orf72‐ ALS / FTD is driven by neuronal excitation and stress

“…The ISR restores cellular homeostasis by activating specific kinases, such as PERK, to phosphorylate eif2a in response to diverse stress stimuli ( the transcription factor ATF4 and reduces general translation by preventing the regeneration of the eif2a ternary complex (composed of eif2a, GTP, and an initiation tRNA (Kwon et al, 2017). A primary candidate was the integrated stress response (ISR) pathway, since many of the non-AUG-dependent inducing stressors we examined in this study ultimately converge and activate this pathway.…”

“…A primary candidate was the integrated stress response (ISR) pathway, since many of the non-AUG-dependent inducing stressors we examined in this study ultimately converge and activate this pathway. The ISR restores cellular homeostasis by activating specific kinases, such as PERK, to phosphorylate eif2a in response to diverse stress stimuli ( the transcription factor ATF4 and reduces general translation by preventing the regeneration of the eif2a ternary complex (composed of eif2a, GTP, and an initiation tRNA (Kwon et al, 2017). Additionally, neuronal activity-stimulated translation and non-conventional translation of mRNAs are highly dependent on the phosphorylation status of eif2a (Chesnokova et al, 2017).…”

A Retrospective on eIF2A—and Not the Alpha Subunit of eIF2

“…c-Src IRES-dependent translation was found to be greatly reduced by the knockdown of eIF2A under stress conditions caused by tunicamycin treatment [93]. The authors also showed that eIF2A specifically interacts with the c-Src IRES and that mutations in the c-Src IRES that impair this interaction, also abrogate the translation of c-Src mRNA under stress conditions, which lead to eIF2α phosphorylation [93]. Furthermore, using filter-binding assays of [ 32 P]-labeled tRNA i the authors demonstrated that eIF2A and c-Src IRES cooperatively facilitate the recruitment of tRNA i onto the 40S ribosomal subunit [93].…”

“…Interestingly, Sung Key Jang has recently reported that eIF2A could be required for the cellular IRES-mediated translation of a non-receptor protein tyrosine kinase c-Src mRNA under conditions of stress [93]. c-Src IRES-dependent translation was found to be greatly reduced by the knockdown of eIF2A under stress conditions caused by tunicamycin treatment [93].…”

“…Interestingly, Sung Key Jang has recently reported that eIF2A could be required for the cellular IRES-mediated translation of a non-receptor protein tyrosine kinase c-Src mRNA under conditions of stress [93]. c-Src IRES-dependent translation was found to be greatly reduced by the knockdown of eIF2A under stress conditions caused by tunicamycin treatment [93]. The authors also showed that eIF2A specifically interacts with the c-Src IRES and that mutations in the c-Src IRES that impair this interaction, also abrogate the translation of c-Src mRNA under stress conditions, which lead to eIF2α phosphorylation [93].…”