TY  - JOUR
AU  - Roiuk, Mykola
AU  - Neff, Marilena
AU  - Teleman, Aurelio
TI  - eIF4E-independent translation is largely eIF3d-dependent.
JO  - Nature Communications
VL  - 15
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2024-01598
SP  - 6692
PY  - 2024
N1  - #EA:B140#LA:B140#
AB  - Translation initiation is a highly regulated step needed for protein synthesis. Most cell-based mechanistic work on translation initiation has been done using non-stressed cells growing in medium with sufficient nutrients and oxygen. This has yielded our current understanding of 'canonical' translation initiation, involving recognition of the mRNA cap by eIF4E1 followed by successive recruitment of initiation factors and the ribosome. Many cells, however, such as tumor cells, are exposed to stresses such as hypoxia, low nutrients or proteotoxic stress. This leads to inactivation of mTORC1 and thereby inactivation of eIF4E1. Hence the question arises how cells translate mRNAs under such stress conditions. We study here how mRNAs are translated in an eIF4E1-independent manner by blocking eIF4E1 using a constitutively active version of eIF4E-binding protein (4E-BP). Via ribosome profiling we identify a subset of mRNAs that are still efficiently translated when eIF4E1 is inactive. We find that these mRNAs preferentially release eIF4E1 when eIF4E1 is inactive and bind instead to eIF3d via its cap-binding pocket. eIF3d then enables these mRNAs to be efficiently translated due to its cap-binding activity. In sum, our work identifies eIF3d-dependent translation as a major mechanism enabling mRNA translation in an eIF4E-independent manner.
KW  - Eukaryotic Initiation Factor-4E: metabolism
KW  - Eukaryotic Initiation Factor-4E: genetics
KW  - Eukaryotic Initiation Factor-3: metabolism
KW  - Eukaryotic Initiation Factor-3: genetics
KW  - Humans
KW  - RNA, Messenger: metabolism
KW  - RNA, Messenger: genetics
KW  - Protein Biosynthesis
KW  - Ribosomes: metabolism
KW  - Protein Binding
KW  - RNA Caps: metabolism
KW  - HEK293 Cells
KW  - Peptide Chain Initiation, Translational
KW  - Cell Cycle Proteins
KW  - Adaptor Proteins, Signal Transducing
KW  - Eukaryotic Initiation Factor-4E (NLM Chemicals)
KW  - Eukaryotic Initiation Factor-3 (NLM Chemicals)
KW  - RNA, Messenger (NLM Chemicals)
KW  - EIF3D protein, human (NLM Chemicals)
KW  - EIF4E protein, human (NLM Chemicals)
KW  - RNA Caps (NLM Chemicals)
KW  - EIF4EBP1 protein, human (NLM Chemicals)
KW  - Cell Cycle Proteins (NLM Chemicals)
KW  - Adaptor Proteins, Signal Transducing (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39107322
DO  - DOI:10.1038/s41467-024-51027-z
UR  - https://inrepo02.dkfz.de/record/292099
ER  -