Chemistry of Life

Molecular genetics, biochemistry

ribosome shunting

Ribosome shunting, or the ribosomal shunt initiation pathway is an alternate viral mechanism of translation initiation in which ribosomes bind to the mRNA in a normal cap-dependent mode, then jump upstream (5'–––→3') of the initiator AUG codon.

Ribosome shunting permits translation of downstream open reading frames in polycistronic mRNAs. The mechanism is utilized by adenoviruses, Sendai virus, and cauliflower mosaic virus. Adenovirus and heat shock mRNAs utilize the altered cap-initiation complex to undergo translation initiation by ribosome shunting.[s] Ribosome shunting is distinguished from another mechanism of viral translation initiation, internal ribosomal entry (IRES), which uses cis-acting mRNA sequences that permit translation initiation within the mRNA rather than at the 5'-cap end.

Ribosomal shunting generates extra information on a single viral mRNA molecule. Ribosome shunting appears less dependent on eIF4F than is scanning-mediated initiation, so it may also support translation of specific mRNAs under conditions in which eIF4F activity is reduced, such as viral infections and heat stress [s2](r).

For some mRNAs, shunting has been shown to require various mRNA elements, some of which are thought to base pair to 18S rRNA. (Gtx is a homeodomain transcription factor.) A short mRNA element in the 5' leader of the Gtx homeodomain mRNA functioned as a ribosomal recruitment site by base pairing to the 18S rRNA. This intermolecular interaction also facilitates ribosomal shunting across two types of obstacles: an upstream AUG codon in excellent context or a stable hairpin structure. Highly efficient shunting occurred when multiple Gtx elements were present upstream of the obstacles, and a single Gtx element was present downstream. Shunting was less efficient, however, when the multiple Gtx elements were present only upstream of the obstacles. In addition, control experiments with mRNAs lacking the upstream elements showed that these results could not be attributed to recruitment by the single downstream element. Experiments in yeast in which the mRNA elements and 18S rRNA sequences were both mutated indicated that shunting required an intact complementary match. The data obtained by this model system provide direct evidence that ribosomal shunting can be mediated by mRNA-rRNA base pairing, a finding that may have general implications for mechanisms of ribosome movement. Chappell SA, Dresios J, Edelman GM, Mauro VP. Ribosomal shunting mediated by a translational enhancer element that base pairs to 18S rRNA. Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9488-93. Epub 2006 Jun 12.

Encephalomyocarditis virus (EMCV) and hepatitis C virus epitomize distinct mechanisms of internal ribosomal entry site (IRES)-mediated initiation. The eIF4A and eIF4G subunits of eIF4F bind immediately upstream of the EMCV initiation codon and promote binding of 43S complexes. EMCV initiation does not involve scanning and does not require eIF1, eIF1A, and the eIF4E subunit of eIF4F. Initiation on some EMCV-like IRESs requires additional noncanonical initiation factors, which alter IRES conformation and promote binding of eIF4A/4G. Initiation on the hepatitis C virus IRES is even simpler: 43S complexes containing only eIF2 and eIF3 bind directly to the initiation codon as a result of specific interaction of the IRES and the 40S subunit. Pestova TV, Kolupaeva VG, Lomakin IB, Pilipenko EV, Shatsky IN, Agol VI,
Hellen CU. Molecular mechanisms of translation initiation in eukaryotes. (Free Full Text Article) Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7029-36.

Translation by ribosome shunting on adenovirus and hsp70 mRNAs facilitated by complementarity to 18S rRNA.
Translation initiation on eukaryotic mRNAs involves 40S ribosome association with mRNA caps (m(7)GpppN), mediated by initiation factor eIF4F. 40S eukaryotic ribosomes and initiation factors undergo 5' scanning to the initiation codon, with no known role for complementarity between eukaryotic 18S rRNA and the 5' noncoding region of mRNAs. We demonstrate that the 5' noncoding region of human adenovirus late mRNAs, known as the tripartite leader, utilizes a striking complementarity to 18S rRNA to facilitate a novel form of translation initiation referred to as ribosome shunting, in which 40S ribosomes bind the cap and bypass large segments of the mRNA to reach the initiation codon. Related elements are also shown to promote ribosome shunting in adenovirus IVa2 intermediate phase mRNA during virus infection and in human heat shock protein 70 (hsp70) mRNA for selective translation during heat shock. The importance of mRNA complementarity to 18S rRNA suggests that ribosome shunting may involve either specific RNA structural features or a prokaryotic-like interaction between mRNA and rRNA.
Yueh A, Schneider RJ. Translation by ribosome shunting on adenovirus and hsp70 mRNAs facilitated by complementarity to 18S rRNA. (Free Full Text Article] Genes Dev. 2000 Feb 15;14(4):414-21.

Selective translation initiation by ribosome jumping in adenovirus-infected and heat-shocked cells. [Genes Dev. 1996] PMID: 8666238
Tethering of eIF4G to adenoviral mRNAs by viral 100k protein drives ribosome shunting. [Genes Dev. 2004] PMID: 15314025
ARC-1, a sequence element complementary to an internal 18S rRNA segment, enhances translation efficiency in plants when present in the leader or intercistronic region of mRNAs. [Nucleic Acids Res. 2004] PMID: 14718549
Ribosomal binding to the internal ribosomal entry site of classical swine fever virus. [RNA. 2000] PMID: 11142379
rRNA-complementarity in the 5' untranslated region of mRNA specifying the Gtx homeodomain protein: evidence that base- pairing to 18S rRNA affects translational efficiency. [Proc Natl Acad Sci U S A. 1999] PMID: 9990025
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