Translation of cIAP2 mRNA is mediated exclusively by a stress-modulated ribosome shunt.
During cellular stress, translation persists or increases for a number of stress-responsive proteins, including cellular inhibitor of apoptosis 2 (cIAP2). The cIAP2 transcript includes a very long (2.78-kb) 5' untranslated region (UTR) with an unusually high number of upstream AUGs (uAUGs), i.e., 64, and a stable predicted secondary structure (DeltaG congruent with -620 kcal/mol) that should completely block conventional scanning-dependent translation initiation. This region did not facilitate internal ribosome entry in vitro or when RNA reporter transcripts were transfected into cells. However, several structural features within the cIAP2 5' UTR were observed to be nearly identical to those required for ribosome shunting in cauliflower mosaic virus RNA and are well conserved in cIAP2 orthologs. Selective mutation revealed that the cIAP2 mRNA mediates translation exclusively via ribosome shunting that bypasses 62 uAUGs. In addition, shunting efficiency was altered by stress and was greatly facilitated by a conserved RNA folding domain (1,470 to 1,877 nucleotides upstream) in a region not scanned by shunting ribosomes. This arrangement suggests that regulation of cIAP2 shunting may involve recruitment of RNA binding proteins to modulate the efficiency of translation initiation.
Sherrill
Kyle W
KW
Department of Molecular Virology and Microbiology, Rm. 860E, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Lloyd
Richard E
RE
D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001483:Base Sequence; D002478:Cells, Cultured / Q000378:metabolism; D004274:DNA, Recombinant / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D017930:Genes, Reporter; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis / Q000235:genetics*; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010441:Peptide Chain Elongation, Translational; D012315:RNA Caps / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D012270:Ribosomes / Q000502:physiology*; D012689:Sequence Homology, Nucleic Acid; D013312:Stress, Physiological / Q000235:genetics* / Q000378:metabolism; D019284:Thapsigargin / Q000633:toxicity; D044767:Ubiquitin-Protein Ligases; D014714:Vertebrates / Q000235:genetics
D020121:5' Untranslated Regions; D004274:DNA, Recombinant; D051034:Inhibitor of Apoptosis Proteins; D012315:RNA Caps; D012333:RNA, Messenger; D019284:Thapsigargin; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases