Dataset Information

Hepatovirus translation requires PDAP1, an eIF4E-binding protein regulating ER stress responses

ABSTRACT: The overexpression and misfolding of viral proteins in the endoplasmic reticulum (ER) may cause cellular stress, thereby inducing cytoprotective proteostatic host responses involving phosphorylation of eIFa. Here, we show the positive-strand RNA virus responsible for infectious hepatitis adopts a stress-resistant, phospho-eIF2a independent mechanism of translation that ensures synthesis of its viral proteins within the infected liver. Cap-independent hepatovirus translation and productive infection in vivo requires PDAP1, a small phosphoprotein with previously unrecognized eIF4E-binding activity. We show PDAP1 interacts also with eIF1A, and is essential for translation of stress-resistant host mRNAs that evade the proteostatic response to ER stress.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Ling Xie

LAB HEAD: Stanley M. Lemon

PROVIDER: PXD052233 | Pride | 2025-05-07

REPOSITORIES: Pride

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			Action	DRS
	20200321_Stan_HAV-PDAP1_11.raw	Raw
	20200321_Stan_HAV-PDAP1_12.raw	Raw
	20200321_Stan_HAV-PDAP1_21.raw	Raw
	20200321_Stan_HAV-PDAP1_22.raw	Raw
	20200321_Stan_HAV_11.raw	Raw

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Publications

Hepatovirus translation requires PDGFA-associated protein 1, an eIF4E-binding protein regulating endoplasmic reticulum stress responses.

Shirasaki Takayoshi T Lenarcic Erik E Misumi Ichiro I Xie Ling L Fusco William G WG Yonish Bryan B Das Anshuman A Kim Hyejeong H Cameron Craig E CE Léger-Abraham Mélissa M Chen Xian X Cullen John M JM Whitmire Jason K JK Li You Y Duncan Joseph A JA Moorman Nathaniel J NJ Lemon Stanley M SM

Science advances 20241120 47

The overexpression and misfolding of viral proteins in the endoplasmic reticulum (ER) may cause cellular stress, thereby inducing a cytoprotective, proteostatic host response involving phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (eIF2α). Here, we show that hepatitis A virus, a positive-strand RNA virus responsible for infectious hepatitis, adopts a stress-resistant, eIF2α-independent mechanism of translation to ensure the synthesis of viral proteins within the inf ...[more]

PMID: 39565848

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Project description:Disruptions of protein homeostasis in the endoplasmic reticulum (ER) elicit activation of the unfolded protein response (UPR), a translation- and transcription-coupled proteostatic stress response pathway. The primary translational control arm of the UPR is initiated by the PERK-dependent phosphorylation of eIF2Î±, leading to a large-scale reprogramming of translation and subsequent activation of an ATF4-mediated transcriptional program. It has remained challenging, however, to accurately evaluate the contribution of each component of the eIF2Î±/ATF4 pathway to the remodelling of transcription and translation. Here, we have used mouse embryonic fibroblasts containing either a knock-in of the non-phosphorylatable eIF2Î± S51A mutant or knock-out for ATF4 by ribosome profiling and mRNA-seq to define the specific contributions of eIF2Î± phosphoryation and ATF4 in controlling the translational and transcriptional components of the UPR. These studies show that the transcriptional and translational targets of each P-eIF2Î±, ATF4, and the other UPR gene expression programs overlapped extensively, leading to a core set of UPR genes whose robust expression in response to ER stress is driven by multiple mechanisms. The identification of other, more factor-specific targets illustrated the potential for functional specialization of the UPR. As the UPR progressed temporally, cells employed distinct combinations of transcriptional and translational mechanisms, initiated by different factors, to adapt to ongoing stress. These effects were accompanied by a buffering effect where changes in mRNA levels were coupled to opposing changes in ribosome loading, a property which makes cooperation between transcription and translation essential to confer robust protein expression. Translational analysis by ribosome profiling and mRNA-seq of PERK pathways mutants during the UPR. Mouse embryonic fibroblasts (MEFs) lacking components of the PERK pathway (eIF2a phosphorylation and ATF4) were subjected to ER stress and analyzed by ribosome profiling.