Regulation of Hypoxia-Inducible Factor 1α during Hypoxia by DAP5-Induced Translation of PHD2.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Bryant, JD; Brown, MC; Dobrikov, MI; Dobrikova, EY; Gemberling, SL; Zhang, Q; Gromeier, M

Published Date

  • June 1, 2018

Published In

Volume / Issue

  • 38 / 11

PubMed ID

  • 29530922

Pubmed Central ID

  • PMC5954183

Electronic International Standard Serial Number (EISSN)

  • 1098-5549

Digital Object Identifier (DOI)

  • 10.1128/MCB.00647-17


  • eng

Conference Location

  • United States