Non-canonical mRNA translation initiation in cell stress and cancer

Abstract

The now well described canonical mRNA translation initiation mechanism of m⁷G 'cap' recognition by cap-binding protein eIF4E and assembly of the canonical pre-initiation complex consisting of scaffolding protein eIF4G and RNA helicase eIF4A has historically been thought to describe all cellular mRNA translation. However, the past decade has seen the discovery of alternative mechanisms to canonical eIF4E mediated mRNA translation initiation. Studies have shown that non-canonical alternate mechanisms of cellular mRNA translation initiation, whether cap-dependent or independent, serve to provide selective translation of mRNAs under cell physiological and pathological stress conditions. These conditions typically involve the global downregulation of canonical eIF4E1/cap-mediated mRNA translation, and selective translational reprogramming of the cell proteome, as occurs in tumor development and malignant progression. Cancer cells must be able to maintain physiological plasticity to acquire a migratory phenotype, invade tissues, metastasize, survive and adapt to severe microenvironmental stress conditions that involve inhibition of canonical mRNA translation initiation. In this review we describe the emerging, important role of non-canonical, alternate mechanisms of mRNA translation initiation in cancer, particularly in adaptation to stresses and the phenotypic cell fate changes involved in malignant progression and metastasis. These alternate translation initiation mechanisms provide new targets for oncology therapeutics development.

Graphical Abstract

Figure 1.

Canonical translation initiation is mediated by the m⁷GTP cap and eIF4E, and cap/eIF4E-independent translation initiation mechanisms are mediated by CITE and IRES mechanisms. (A) Canonical cap/eIF4E-dependent translation initiation involves recognition of the m⁷GTP cap by eIF4E in association with eIF4GI or II and eIF4A (the eIF4F complex). eIF3 interacts with eIF4GI or II which in turn recruits the 40S ribosome subunit and the ternary complex (3ºC) consisting of eIF2-GTP-Met-tRNAi to form the pre-initiation complex (PIC). Following 40S ribosome subunit scanning to the initiation codon (AUG), the 60S ribosome subunit joins (not shown). (B) CITE cap/eIF4E-independent but 5′UTR dependent translation involves structural elements or modifications in the 5′UTR that are thought to bind directly to certain translation initiation factors that contain RNA binding motifs such as eIF4GI, II, or III, and/or eIF3, without the need for eIF4E and cap interaction, but in close proximity to the cap. (C) Cellular IRES-mediated mRNA translation initiation is thought to involve stable secondary hairpin structures anywhere in the mRNA (although generally in the 5′UTR) that can directly recruit the 40S small ribosomal subunit in the absence of cap and eIF4E interaction. IRES-mediated initiation typically requires interaction with IRES trans-acting factors (ITAFs), and either eIF4GI, eIF4GII or eIF4GIII (DAP5/eIF4G2), eIF3 and often eIF4A. DAP5 in particular has been shown to assist in cellular IRES-mediated mRNA translation. The Figure was partly generated using Biorender under the agreement number UO26MCB80P (www.Biorender.com).

Figure 2.

eIF4G family member proteins. Shown are the three human eIF4G proteins. eIF4GI protein (eIF4G1 gene) contains binding domains for Poly(A)-Binding Protein (PABP), eIF4E, two binding sites for eIF4A, three HEAT motifs (flexible helix-turn-helix anti-parallel α-helices), an eIF3 binding site, an MA3 protein binding domain (α-helical repeats), and a W2 protein binding domain (two invariant tryptophan amino acids and α-helices). eIF4GII protein (eIF4G3 gene) is highly homologous to eIF4GI but is typically expressed only in low amounts in most cells, and eIF4GIII protein also known as DAP5 (eIF4G2 gene) which is about 65% homologous to eIF4GI and lacks PABP and eIF4E interaction sites. The Figure was partly generated using Biorender under the agreement number TZ26DM9P6S (www.Biorender.com).

Figure 3.

Non-canonical eIF3 and/or DAP5-dependent mRNA translation initiation mechanisms. (A) DAP5/eIF3d non-canonical cap-dependent but eIF4E-independent mRNA translation initiation involves recognition of the cap by eIF3d/DAP5 complexes that recruit eIF4A, eIF3, the 40S ribosome, and eIF2-GTP-Met-tRNAi ternary complex (3ºC) as an alternate form of the PIC. 40S ribosome subunit scanning, joining of the 60S ribosome subunit at the AUG are thought to be the same as canonical eIF4F-mediated initiation. (B) eIF3d/eIF3 non-canonical cap-dependent but eIF4E-independent mRNA translation,. This mechanism involves a specialized 5′ hairpin structure adjacent to the cap and cap-binding by eIF3d, presumably in association with the eIF3 complex, recruitment of the 40S ribosome subunit and the ternary complex. Given the absence of an eIF4G paralog, the recruitment of eIF4A remains uncertain. (C) m⁶A mediated cap-independent mRNA translation initiation involves recruitment of eIF3 to m⁶A marks in the 5′UTR. eIF3 in turn recruits the 40S ribosome and the ternary complex. The figure was partly generated using Biorender under the agreement number VC26ML5TN0 (www.Biorender.com).