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The integrated stress response regulates BMP signalling through effects on translation.

Published version
Peer-reviewed

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Authors

Malzer, Elke 
Dominicus, Caia S 
Dickens, Jennifer 
Mookerjee, Souradip  ORCID logo  https://orcid.org/0000-0003-4904-1324

Abstract

Background: Developmental pathways must be responsive to the environment. Phosphorylation of eIF2α enables a family of stress sensing kinases to trigger the integrated stress response (ISR), which has pro-survival and developmental consequences. Bone Morphogenetic Proteins (BMPs) regulate multiple developmental processes in organisms from insects to mammals. Results: 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 eIF2α 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. Conclusion: These results identify a novel mechanism by which the ISR modulates BMP signaling during development.

Description

Keywords

Animals, Drosophila, Protein Kinases, Drosophila Proteins, Bone Morphogenetic Proteins, Eukaryotic Initiation Factor-2, Signal Transduction, Gene Expression Regulation, Phosphorylation

Journal Title

BMC biology

Conference Name

Journal ISSN

1741-7007
1741-7007

Volume Title

16

Publisher

BioMed Central
Sponsorship
MRC (G1002610)
Academy of Medical Sciences (unknown)
Cambridge University Hospitals NHS Foundation Trust (CUH) (3819-1617-14)
Addenbrooke's Charitable Trust (ACT) (13/17 B(v) 900908/9980)
MRC (MR/R009120/1)
MRC (G0601840)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (093026/Z/10/Z)