整体应激反应通过对翻译的影响来调节 BMP 信号转导。

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

机构信息

Cambridge Institute for Medical Research (CIMR), University of Cambridge, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 0XY, UK.

Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Rd, Cambridge, CB2 0SP, UK.

出版信息

BMC Biol. 2018 Apr 3;16(1):34. doi: 10.1186/s12915-018-0503-x.

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 signalling 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 impairs developmental BMP signalling in flies. In cells, inhibition of translation by GCN2 blocks downstream BMP signalling. Moreover, loss of d4E-BP, a target of crc, augments BMP signalling in vitro and rescues tissue development in vivo.

CONCLUSION

These results identify a novel mechanism by which the ISR modulates BMP signalling during development.

背景

发育途径必须对环境做出反应。eIF2α 的磷酸化使一系列应激感应激酶能够触发整合应激反应（ISR），这具有促进生存和发育的后果。骨形态发生蛋白（BMPs）调节从昆虫到哺乳动物等生物体的多种发育过程。

结果

在这里，我们在果蝇中表明，GCN2 通过直接影响翻译和间接通过转录因子 crc（dATF4）来拮抗 BMP 信号。组成性激活的 GCN2 的表达或 eIF2α 磷酸酶 dPPP1R15 的缺失会损害果蝇中的发育 BMP 信号。在细胞中，GCN2 抑制翻译会阻断下游的 BMP 信号。此外，d4E-BP（crc 的靶标）的缺失会增强体外的 BMP 信号，并在体内挽救组织发育。