Herp is dually regulated by both the endoplasmic reticulum stress-specific branch of the unfolded protein response and a branch that is shared with other cellular stress pathways.
The mammalian unfolded protein response (UPR) includes two major branches: one(s) specific to ER stress (Ire1/XBP-1 and ATF6-dependent), and one(s) shared by other cellular stresses (PERK/eIF-2alpha phosphorylation-dependent). Here, we demonstrate that the ER-localized protein Herp represents a second target, in addition to CHOP, that is dually regulated by both the shared and the ER stress-specific branches during UPR activation. For the first time, we are able to assess the contribution of each branch of the UPR in the induction of these targets. We demonstrate that activation of the shared branch of the UPR alone was sufficient to induce Herp and CHOP. ATF4 was not required during ER stress when both branches were used but did contribute significantly to their induction. Conversely, stresses that activated only the shared branch of the UPR were completely dependent on ATF4 for CHOP and Herp induction. Thus, the shared and the ER stress-specific branches of the UPR diverge to regulate two groups of targets, one that is ATF6 and Ire1/XBP-1-dependent, which includes BiP and XBP-1, and another that is eIF-2alpha kinase-dependent, which includes ATF4 and GADD34. The two branches also converge to maximally up-regulate targets like Herp and CHOP. Finally, our studies reveal that a PERK-dependent target other than ATF4 is contributing to the cross-talk between the two branches of the UPR that has previously been demonstrated.
Ma
Yanjun
Y
Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Hendershot
Linda M
LM
D051701:Activating Transcription Factor 4; D051696:Activating Transcription Factors; D000818:Animals; D001483:Base Sequence; D001798:Blood Proteins / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D003470:Culture Media; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006360:Heat-Shock Proteins; D007930:Leucine / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D017510:Protein Folding; D020218:Response Elements; D015534:Trans-Activators / Q000378:metabolism; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism*
D051696:Activating Transcription Factors; C081452:Atf4 protein, mouse; D001798:Blood Proteins; D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D003470:Culture Media; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; C415829:Herpud1 protein, mouse; D008565:Membrane Proteins; D018832:Molecular Chaperones; D015534:Trans-Activators; D014157:Transcription Factors; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; D007930:Leucine