Regulation of hypoxiainducible factor 1a during hypoxia by DAP5- induced translation of PHD2

Jeffrey D. Bryant, Michael C. Brown, Mikhail I. Dobrikov, Elena Y. Dobrikova, Sarah L. Gemberling, Qing Zhang, Matthias Gromeier

Research output: Contribution to journalArticle

4 Scopus citations

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 languageEnglish (US)
Article numbere00647-17
JournalMolecular and cellular biology
Volume38
Issue number11
DOIs
Publication statusPublished - Jun 1 2018
Externally publishedYes

    Fingerprint

Keywords

  • DAP5
  • EIF2β
  • HIF-1α
  • Hypoxia
  • PHD2
  • Translation initiation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Bryant, J. D., Brown, M. C., Dobrikov, M. I., Dobrikova, E. Y., Gemberling, S. L., Zhang, Q., & Gromeier, M. (2018). Regulation of hypoxiainducible factor 1a during hypoxia by DAP5- induced translation of PHD2. Molecular and cellular biology, 38(11), [e00647-17]. https://doi.org/10.1128/MCB.00647-17