The eIF4G-homolog p97 can activate translation independent of caspase cleavage.
The eukaryotic initiation factor (eIF) 4G family plays a central role during translation initiation, bridging between the 5' and 3' ends of the mRNA via its N-terminal third while recruiting other factors and ribosomes through its central and C-terminal third. The protein p97/NAT1/DAP5 is homologous to the central and C-terminal thirds of eIF4G. p97 has long been considered to be a translational repressor under normal cellular conditions. Further, caspase cleavage liberates a p86 fragment that is thought to mediate cap-independent translation in apoptotic cells. We report here that, surprisingly, human p97 is polysome associated in proliferating cells and moves to stress granules in stressed, nonapoptotic cells. Tethered-function studies in living cells show that human p97 and p86 both can activate translation; however, we were unable to detect polysome association of p86 in apoptotic cells. We further characterized the zebrafish orthologs of p97, and found both to be expressed throughout embryonic development. Their simultaneous knockdown by morpholino injection led to impaired mesoderm formation and early embryonic lethality, indicating conservation of embryonic p97 function from fish to mammals. These data indicate that full-length p97 is a translational activator with essential role(s) in unstressed cells, suggesting a reassessment of current models of p97 function.
Nousch
Marco
M
Molecular Genetics Program, Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, NSW, Australia.
Reed
Victoria
V
Bryson-Richardson
Robert J
RJ
Currie
Peter D
PD
Preiss
Thomas
T
D000595:Amino Acid Sequence; D000818:Animals; D020169:Caspases / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000737:chemistry; D039603:Eukaryotic Initiation Factor-4G / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D011132:Polyribosomes / Q000737:chemistry / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology
C491300:EIF4G2 protein, human; D039603:Eukaryotic Initiation Factor-4G; D012333:RNA, Messenger; D012097:Repressor Proteins; D029961:Zebrafish Proteins; C518887:eif4g2a protein, zebrafish; C518888:eif4g2b protein, zebrafish; D020169:Caspases