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.

Figure 1.

A model conveying the different mechanisms of noncanonical translation initiation. The locations of the cis-acting elements (red dashed lines), the open reading frames ([ORFs], blue rectangles), and 5′ and 3′ untranslated regions ([UTRs], black lines) are indicated. (A) Viral protein linked to the genome (VPg) rather than a 5′ cap. (B) Translation initiator of short 5′UTR (TISU) element with the start codon underlined. (C) m⁶A modification. (D) Internal ribosomal entry site (IRES): the intergenic region (IGR) IRES is shown. (E) 3′ Cap-independent translation element (CITE): barley yellow dwarf virus-like translation element (BTE) CITE in the 3′UTR is shown forming a kissing-loop (dotted line) interaction with a stem loop in the 5′UTR. (F) Ribosomal shunting: cauliflower mosaic virus (CaMV) ribosomal shunt is shown; the highly structured region promotes shunting of the 40S from the “donor” site to a downstream “acceptor” site for initiation.