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

Author:

Bryant Jeffrey D.12,Brown Michael C.2,Dobrikov Mikhail I.2,Dobrikova Elena Y.2,Gemberling Sarah L.2,Zhang Qing34,Gromeier Matthias12

Affiliation:

1. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA

2. Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA

3. Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA

4. Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

Abstract

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.

Funder

U.S. Department of Health and Human Services

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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