miR-190 enhances HIF-dependent responses to hypoxia in Drosophila by inhibiting the prolyl-4-hydroxylase Fatiga

BERTOLIN A.P; GÁNDARA L; PERRIMON N.; DE LELLA EZCURRA A.L; KATZ MJ,; LUSCHNIG S; WAPPNER P; KIM K; MISRA T; MELANI M

PLOS GENETICS

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2016 vol. 12 p. 1 - 18

1553-7390

Cellular and systemic responses to low oxygen levels are principally mediated by Hypoxia Inducible Factors (HIFs), a family of evolutionary conserved heterodimeric transcription factors, whose alpha- and beta-subunits belong to the bHLH-PAS family. In normoxia, HIF is hydroxylated by specific prolyl-4-hydroxylases, targeting it for proteasomal degradation, while in hypoxia the activity of these hydroxylases decreases due to low oxygen availability, leading to HIF accumulation and expression of HIF target genes. To identify microRNAs required for maximal HIF activity, we conducted an overexpression screen in Drosophila melanogaster, evaluating the induction of a HIF transcriptional reporter. miR-190 overexpression enhanced HIF-dependent biological responses, including terminal sprouting of the tracheal system, while in miR-190 loss of function embryos the hypoxic response was impaired. In hypoxic conditions, miR-190 expression was upregulated and required for induction of HIF target genes by directly inhibiting the HIF prolyl-4-hydroxylase Fatiga. Thus, miR-190 is a novel regulator of the hypoxia response that represses the oxygen sensor Fatiga, leading to HIF stabilization and enhancement of hypoxic responses.