An alternative mechanism of eukaryotic translation initiation.
Cell stress activates signaling pathways, allowing cells to choose between survival and apoptosis. Translation plays a critical role in balancing this choice by allowing for rapid and physiologically responsive changes in de novo gene expression. The steady-state abundance of cellular inhibitor of apoptosis 2 (cIAP2) is increased in response to various cell stresses. This modular protein contains baculoviral IAP repeat (BIR) motifs and ubiquitin protein ligase (E3) activity, which allows it to bind directly to caspases and to modulate activation of the transcription factor, nuclear factor kappaB (NF-kappaB). The messenger RNA (mRNA) encoding cIAP2 is a large 5.5-kb transcript, with a highly structured 5' untranslated region (5'UTR) also containing 64 upstream initiation codons ahead of the true start codon. cIAP2 employs an unusual cap-dependent mechanism of ribosome shunting to bypass the majority of the inhibitory elements in the 5'UTR, a mechanism first described for plant pararetroviruses. Furthermore, in mammalian cells, this poorly understood mechanism of translation for cIAP2 is enhanced during mild stress in the absence of pararetrovirus-encoded proteins known to be essential for this process in plant cells. Here, we discuss how cIAP2 might utilize the stress-mediated shunt process in the absence of viral proteins, which suggests a more widespread role for canonical initiation factors, internal ribosome entry sequence-specific trans-acting factors, and mRNA structure in translational control during stress.
Morley
Simon J
SJ
Department of Biochemistry, School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK. s.j.morley@sussex.ac.uk
Coldwell
Mark J
MJ
D002455:Cell Division; D002468:Cell Physiological Phenomena; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics; D006801:Humans; D008957:Models, Genetic; D010442:Peptide Chain Initiation, Translational / Q000502:physiology*; D014176:Protein Biosynthesis / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D012270:Ribosomes / Q000502:physiology*; D015398:Signal Transduction; D013314:Stress, Mechanical
D020717:Eukaryotic Initiation Factor-2B; D012333:RNA, Messenger