Integated Stress Response in Drosophila
Conferencia de Don Ryoo
16 de Agosto del 2017 de 12:00 hrs
Cells respond to various types of stress by adjusting their gene expression profile. While transcriptional responses to such stress is well-documented, such change in transcriptional profiles often do not correlate with their protein synthesis patterns as stressed cells frequently activate mRNA translational inhibitors. In our effort to understand how translation and transcription are coupled in response to stress, we study the Integrated Stress Response. Specifically, this pathway is initiated by stress-activated kinases that phosphorylate and inhibit the translational initiation factor eIF2a. While such condition attenuates general translation, a few transcripts paradoxically enhance their translation rate in response. One such factor induced after eIF2a phosphorylation is the transcription factor ATF4. We recently found that ATF4 induces a second translational inhibitor 4E-BP, thereby inhibiting eIF-4E-mediated cap-dependent translation. 4E-BP in Drosophila had been reported as a gene whose expression is induced by dietary restriction of amino acids, and also, in response to bacterial infection. We find that Integrated Stress Response is in fact required for 4E-BP induction under those conditions. Moreover, we find that key transcripts that are induced under these conditions are not efficiently inhibited by 4E-BP, due to the presence of Internal Ribosome Entry Sites (IRES) in their 5’ UTR. Consistently, mutations in the mediators of the Integrated Stress Response makes Drosophila more vulnerable to dietary restriction of amino acids and to pathogenic bacterial infection. These results indicate that many stress responsive transcripts have specific regulatory sequences that ensure their efficient transcription and translation in stressed cells where general translation is inhibited.