Noncanonical Translation Initiation in Eukaryotes

Abstract

The vast majority of eukaryotic messenger RNAs (mRNAs) initiate translation through a canonical, cap-dependent mechanism requiring a free 5' end and 5' cap and several initiation factors to form a translationally active ribosome. Stresses such as hypoxia, apoptosis, starvation, and viral infection down-regulate cap-dependent translation during which alternative mechanisms of translation initiation prevail to express proteins required to cope with the stress, or to produce viral proteins. The diversity of noncanonical initiation mechanisms encompasses a broad range of strategies and cellular cofactors. Herein, we provide an overview and, whenever possible, a mechanistic understanding of the various noncanonical mechanisms of initiation used by cells and viruses. Despite many unanswered questions, recent advances have propelled our understanding of the scope, diversity, and mechanisms of alternative initiation.

Translational Control in Virus-Infected Cells

“…Viral mRNA 5 0 ends may be uncapped, protein-linked, modified by viral capping enzymes to contain a 5 0 methyl-7-GTP (m 7 GTP) cap, or derived from host mRNA 5 0 terminal fragments that are naturally capped (Decroly et al 2012). Uncapped viral mRNAs deploy specialized genome elements to recruit 40S ribosomal subunits that support translation even when canonical cap-dependent translation is impaired (Kwan and Thompson 2018). Polyadenylated 3 0 ends are generally template-encoded for RNAviruses or replaced by an element that recruits a viral 3 0 terminal binding protein (Poon et al 1999;Deo et al 2002; Kempf and Barton 2015).…”

“…Uncapped poliovirus mRNA contains a specialized, cis-acting RNA internal ribosome entry site (IRES) in the 5 0 UTR. In contrast to canonical cap-dependent initiation where 40S ribosomes load onto the mRNA 5 0 end, highly structured IRES elements enable ribosome recruitment to specific internal sites within viral RNA (Kwan and Thompson 2018). IRESs were first discovered in poliovirus and EMCV where they allow translation initiation of uncapped, single-stranded (+)-sense RNA viral genomes immediately upon release into the cytoplasm (Jang et al 1988;Pelletier and Sonenberg 1988).…”

SARS-CoV-2 codon usage bias downregulates host expressed genes with similar codon usage

“…This analysis reveals that codon usage could promote extensive changes in the translation machinery of the host in agreement with previous report in CACO-2 cells (4). Its is known that when canonical translation is impaired, as part of the host defence program, specific 40S ribosomal subunits are needed to support uncapped viral mRNA translation (22).…”

ILF3 contributes to the establishment of the antiviral type I interferon program

“…TOP mRNAs are enriched for genes encoding protein synthesis factors, such as ribosomal proteins, and their translation is regulated during stress growth conditions by the mTOR pathway (46). On the other hand, IRES-containing mRNAs bypass the need of 5’end cap structure to initiate translation and directly recruit the ribosome internally to the mRNA (47). These results were validated by qRT-PCR, confirming a reduction in the production of the ISGs, IFTI2 , ISG15 , CCL5 and CXCL10 in the absence of ILF3 ( Figure 1D ).…”