The integrated stress response regulates BMP signaling through effects on translation

Developmental pathways must be responsive to the environment. Phosphorylation of eIF2 enables a family of stress sensing kinases to trigger the integrated stress response (ISR), which has pro-survival and developmental consequences. Mutations of the ISR kinase GCN2 have been implicated in the development of pulmonary arterial hypertension, a disorder known to be associated with defects of BMP signaling, but how the ISR and BMP signaling might interact is unknown. Here we show in Drosophila that GCN2 antagonises BMP signaling through direct effects on translation and indirectly via the transcription factor crc (dATF4). Expression of a constitutively active GCN2 or loss of the eIF2 phosphatase dPPP1R15 impair developmental BMP signaling in flies. In cells, inhibition of translation by GCN2 blocks downstream BMP signaling. Moreover, loss of d4E-BP, a target of crc, augments BMP signaling in vitro and rescues tissue development in vivo. These results identify a novel mechanism by which the ISR modulates BMP signaling during development. Since abnormalities of both GCN2 and BMP signaling lead to pulmonary hypertension, these findings may have wider relevance for the development of therapies for this disease.