TY - JOUR
T1 - The DEAD-box RNA helicase Ded1 has a role in the translational response to TORC1 inhibition
AU - Aryanpur, Peyman P.
AU - Renner, David M.
AU - Rodela, Emily
AU - Mittelmeier, Telsa M.
AU - Byrd, Aaron
AU - Bolger, Timothy A.
N1 - Funding Information:
We thank Roy Parker, Angela Hilliker, Eckhard Jankowsky, and Tom Dever for reagents and members of the Bolger and J.R. Buchan laboratories for helpful advice and discussions. This work was supported by the American Cancer Society (RSG-13-263-01-RMC to T.A.B.) and the Arizona Biomedical Research Commission (ADHS14-082993 to T.A.B.).
Publisher Copyright:
© 2019 Aryanpur et al.
PY - 2019/8/1
Y1 - 2019/8/1
N2 - Ded1 is a DEAD-box RNA helicase with essential roles in translation initiation. It binds to the eukaryotic initiation factor 4F (eIF4F) complex and promotes 48S preinitiation complex assembly and start-site scanning of 5′ untranslated regions of mRNAs. Most prior studies of Ded1 cellular function were conducted in steady-state conditions during nutrient-rich growth. In this work, however, we examine its role in the translational response during target of rapamycin (TOR)C1 inhibition and identify a novel function of Ded1 as a translation repressor. We show that C-terminal mutants of DED1 are defective in down-regulating translation following TORC1 inhibition using rapamycin. Furthermore, following TORC1 inhibition, eIF4G1 normally dissociates from translation complexes and is degraded, and this process is attenuated in mutant cells. Mapping of the functional requirements for Ded1 in this translational response indicates that Ded1 enzymatic activity and interaction with eIF4G1 are required, while homo-oligomerization may be dispensable. Our results are consistent with a model wherein Ded1 stalls translation and specifically removes eIF4G1 from translation preinitiation complexes, thus removing eIF4G1 from the translating mRNA pool and leading to the codegradation of both proteins. Shared features among DED1 orthologues suggest that this role is conserved and may be implicated in pathologies such as oncogenesis.
AB - Ded1 is a DEAD-box RNA helicase with essential roles in translation initiation. It binds to the eukaryotic initiation factor 4F (eIF4F) complex and promotes 48S preinitiation complex assembly and start-site scanning of 5′ untranslated regions of mRNAs. Most prior studies of Ded1 cellular function were conducted in steady-state conditions during nutrient-rich growth. In this work, however, we examine its role in the translational response during target of rapamycin (TOR)C1 inhibition and identify a novel function of Ded1 as a translation repressor. We show that C-terminal mutants of DED1 are defective in down-regulating translation following TORC1 inhibition using rapamycin. Furthermore, following TORC1 inhibition, eIF4G1 normally dissociates from translation complexes and is degraded, and this process is attenuated in mutant cells. Mapping of the functional requirements for Ded1 in this translational response indicates that Ded1 enzymatic activity and interaction with eIF4G1 are required, while homo-oligomerization may be dispensable. Our results are consistent with a model wherein Ded1 stalls translation and specifically removes eIF4G1 from translation preinitiation complexes, thus removing eIF4G1 from the translating mRNA pool and leading to the codegradation of both proteins. Shared features among DED1 orthologues suggest that this role is conserved and may be implicated in pathologies such as oncogenesis.
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U2 - 10.1091/mbc.E18-11-0702
DO - 10.1091/mbc.E18-11-0702
M3 - Article
C2 - 31141444
AN - SCOPUS:85070848166
SN - 1059-1524
VL - 30
SP - 2171
EP - 2184
JO - Molecular biology of the cell
JF - Molecular biology of the cell
IS - 17
ER -