Talk abstracts
Talk on Saturday 03:45-04:05pm submitted by Deepika Vasudevan
Translational induction of ATF4 mRNA during stress requires noncanonical initiation factors eIF2D and DENR
Deepika Vasudevan (Cell Biology, NYU School of Medicine), Sarah D. Neuman (Dept. of Pharmaceutical Sciences, University of Wisconsin-Madison), Amy Yang (Cell Biology, NYU School of Medicine), Arash Bashirullah (Dept. of Pharmaceutical Sciences, University of Wisconsin-Madison), Hyung Don Ryoo (Cell Biology, NYU School of Medicine)
Abstract:
Certain conditions of cellular stress impose restrictions on mRNA translation by activating stress response kinases that phospho-inactivate the α-subunit of the initiator methionine-carrying complex, eIF2. Such restrictive translation conditions paradoxically stimulate the synthesis of the transcription factor ATF4 to induce a stress responsive gene expression program. In a Drosophila RNAi screen, we discovered eIF2D as a regulator of ATF4, and subsequently validated this observation with two independent eIF2D mutant alleles. Based on domain analysis, we found that the eIF2D homolog complex, DENR-MCTS1, also exerted similar effects on ATF4. While deletion of eIF2D or DENR had little effect on ATF4 mRNA levels, it resulted in marked decrease of an ATF4 5’UTR-dsRed reporter in response to amino acid deprivation or ER stress. Disrupting the tRNA-binding activity of eIF2D also resulted in decreased expression of the ATF4 5’UTR-dsRed reporter. Taken together, these data suggest that eIF2D and DENR-MCTS1 are non-canonical initiation factors required for the translational induction of ATF4. Consistently, loss of eIF2D and DENR in Drosophila results in increased vulnerability to amino acid deprivation, susceptibility to retinal degeneration caused by ER stress, and developmental defects similar to ATF4 mutants. eIF2D and DENR deficient human cells also show impaired ATF4 protein induction in response to ER stress, indicating that such regulation is conserved in higher organisms.
Keywords: Integrated Stress Response, reinitiation, eIF2D