Abstract
Death-associated protein 5 (DAP5) is an atypical isoform of the translation initiation scaffolds eukaryotic initiation factor 4GI (eIF4GI) and eIF4GII (eIF4GI/II), which recruit mRNAs to ribosomes in mammals. Unlike eIF4GI/II, DAP5 binds eIF2β, a subunit of the eIF2 complex that delivers methionyl-tRNA to ribosomes. We discovered that DAP5:eIF2β binding depends on specific stimuli, e.g., protein kinase C (PKC)- Raf-extracellular signal-regulated kinase 1/2 (ERK1/2) signals, and determines DAP5's influence on global and template-specific translation. DAP5 depletion caused an unanticipated surge of hypoxia-inducible factor 1α (HIF-1α), the transcription factor and master switch of the hypoxia response. Physiologically, the hypoxia response is tempered through HIF-1α hydroxylation by the oxygen-sensing prolyl hydroxylase-domain protein 2 (PHD2) and subsequent ubiquitination and degradation. We found that DAP5 regulates HIF-1α abundance through DAP5:eIF2β-dependent translation of PHD2. DAP5: eIF2-induced PHD2 translation occurred during hypoxia-associated protein synthesis repression, indicating a role as a safeguard to reverse HIF-1α accumulation and curb the hypoxic response.
Original language | English (US) |
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Article number | e00647-17 |
Journal | Molecular and cellular biology |
Volume | 38 |
Issue number | 11 |
DOIs | |
State | Published - Jun 1 2018 |
Externally published | Yes |
Keywords
- DAP5
- EIF2β
- HIF-1α
- Hypoxia
- PHD2
- Translation initiation
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology