Monocistronic mRNAs containing defective hepatitis C virus-like picornavirus internal ribosome entry site elements in their 5' untranslated regions are efficiently translated in cells by a cap-dependent mechanism
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Monocistronic mRNAs containing defective hepatitis C virus-like picornavirus internal ribosome entry site elements in their 5' untranslated regions are efficiently translated in cells by a cap-dependent mechanism. / Belsham, Graham J; Nielsen, Inge; Normann, Preben; Royall, Elizabeth; Roberts, Lisa O.
I: R N A, Bind 14, Nr. 8, 08.2008, s. 1671-80.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Monocistronic mRNAs containing defective hepatitis C virus-like picornavirus internal ribosome entry site elements in their 5' untranslated regions are efficiently translated in cells by a cap-dependent mechanism
AU - Belsham, Graham J
AU - Nielsen, Inge
AU - Normann, Preben
AU - Royall, Elizabeth
AU - Roberts, Lisa O
PY - 2008/8
Y1 - 2008/8
N2 - The initiation of protein synthesis on mRNAs within eukaryotic cells is achieved either by a 5' cap-dependent mechanism or through internal initiation directed by an internal ribosome entry site (IRES). Picornavirus IRES elements, located in the 5' untranslated region (5'UTR), contain extensive secondary structure and multiple upstream AUG codons. These features can be expected to inhibit cap-dependent initiation of translation. However, we have now shown that certain mutant hepatitis C virus-like picornavirus IRES elements (from porcine teschovirus-1 and avian encephalomyelitis virus), which are unable to direct internal initiation, are not significant barriers to efficient translation of capped monocistronic mRNAs that contain these defective elements within their 5'UTRs. Moreover, the translation of these mRNAs is highly sensitive to the expression of an enterovirus 2A protease (which induces cleavage of eIF4G) and is also inhibited by hippuristanol, a specific inhibitor of eIF4A function, in contrast to their parental wild-type IRES elements. These results provide a possible basis for the evolution of viral IRES elements within the context of functional mRNAs that are translated by a cap-dependent mechanism.
AB - The initiation of protein synthesis on mRNAs within eukaryotic cells is achieved either by a 5' cap-dependent mechanism or through internal initiation directed by an internal ribosome entry site (IRES). Picornavirus IRES elements, located in the 5' untranslated region (5'UTR), contain extensive secondary structure and multiple upstream AUG codons. These features can be expected to inhibit cap-dependent initiation of translation. However, we have now shown that certain mutant hepatitis C virus-like picornavirus IRES elements (from porcine teschovirus-1 and avian encephalomyelitis virus), which are unable to direct internal initiation, are not significant barriers to efficient translation of capped monocistronic mRNAs that contain these defective elements within their 5'UTRs. Moreover, the translation of these mRNAs is highly sensitive to the expression of an enterovirus 2A protease (which induces cleavage of eIF4G) and is also inhibited by hippuristanol, a specific inhibitor of eIF4A function, in contrast to their parental wild-type IRES elements. These results provide a possible basis for the evolution of viral IRES elements within the context of functional mRNAs that are translated by a cap-dependent mechanism.
KW - 5' Untranslated Regions/chemistry
KW - Eukaryotic Initiation Factor-4G/antagonists & inhibitors
KW - Humans
KW - Peptide Chain Initiation, Translational
KW - Picornaviridae/chemistry
KW - Protein Biosynthesis
KW - RNA Caps/metabolism
KW - RNA, Messenger/chemistry
KW - Regulatory Sequences, Ribonucleic Acid
KW - Ribosomes/metabolism
KW - Sterols/pharmacology
U2 - 10.1261/rna.1039708
DO - 10.1261/rna.1039708
M3 - Journal article
C2 - 18567818
VL - 14
SP - 1671
EP - 1680
JO - RNA
JF - RNA
SN - 1355-8382
IS - 8
ER -
ID: 257918409