MassIVE MSV000099506

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4EHP and NELF-E regulate physiological ATF4 induction and proteostasis in disease models of Drosophila

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Description

Cells adapt to proteostatic and metabolic stresses, in part, by triggering the phosphorylation of eIF2a and the synthesis of ATF4. eIF2a phosphorylation facilitates ATF4 translation through regulatory elements at ATF4 mRNAs 5 leader. In addition to eIF2a, ATF4 induction requires other regulators that remain poorly understood. Here, we report an ATF4 regulatory network consisting of eIF4E-Homologous Protein (4EHP), NELF-E, the 40S ribosome, and eIF3 subunits. Specifically, we found that the mRNA cap-binding protein, 4EHP, was required for ATF4 signaling in the Drosophila larval fat body and in disease models associated with abnormal ATF4 signaling. NELF-E mRNA, encoding a regulator of pol II-mediated transcription, was identified as a top interactor of 4EHP in a TRIBE (Targets of RNA Binding through Editing) screen. Quantitative proteomics analysis revealed that the knockdown of NELF-E or 4EHP commonly reduced several subunits of the 40S ribosome (RpS) and the eIF3 translation initiation factor. Moreover, reduction of NELF-E, 4EHP, RpS12, eIF3l, or eIF3h suppressed the expression of ATF4 and its target genes. These results uncover a previously unrecognized ATF4 regulatory network consisting of 4EHP and NELF-E that impacts proteostasis during normal development and in disease models. [doi:10.25345/C5JW87157] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: eIF2a ; NELF-E ; ATF4 ; Drosophila ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Beatrix M Ueberheide, NYU Langone Grossman School of Medicine, USA
Submitting User: KanshinED1
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