title: An atypical unfolded protein response in heat shocked cells.
abstract: BACKGROUND
  The heat shock response (HSR) and the unfolded protein response (UPR) are both activated by proteotoxic stress, although in different compartments, and share cellular resources. How these resources are allocated when both responses are active is not known. Insight in possible crosstalk will help understanding the consequences of failure of these systems in (age-related) disease.
  
  
  RESULTS
  In heat stressed HEK293 cells synthesis of the canonical UPR transcription factors XBP1s and ATF4 was detected as well as HSF1 independent activation of the promoters of the ER resident chaperones HSPA5 (BiP) and DNAJB9 (ERdj4). However, the heat stress activation of the DNAJB9 promoter, a XBP1s target, was not blocked in cells expressing a dominant negative IRE1α mutant, and thus did not require XBP1s. Furthermore, the DNA element required for heat stress activation of the DNAJB9 promoter is distinct from the ATF4 and ATF6 target elements; even though inhibition of eIF2α phosphorylation resulted in a decreased activation of the DNAJB9 promoter upon heat stress, suggesting a role for an eIF2α phosphorylation dependent product.
  
  
  CONCLUSIONS
  The initial step in the UPR, synthesis of transcription factors, is activated by heat stress but the second step, transcriptional transactivation by these factors, is blocked and these pathways of the UPR are thus not productive. Expression of canonical ER chaperones is part of the response of heat stressed cells but another set of transcription factors has been recruited to regulate expression of these ER chaperones.
authors.affiliation: Department of Biomolecular Chemistry, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Lonneke
authors.initials: L
authors.lastname: Heldens
authors.forename: Sanne M M
authors.initials: SM
authors.lastname: Hensen
authors.forename: Carla
authors.initials: C
authors.lastname: Onnekink
authors.forename: Siebe T
authors.initials: ST
authors.lastname: van Genesen
authors.forename: Ron P
authors.initials: RP
authors.lastname: Dirks
authors.forename: Nicolette H
authors.initials: NH
authors.lastname: Lubsen
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D017930:Genes, Reporter / Q000235:genetics; D057809:HEK293 Cells; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018869:Heat-Shock Response / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D018832:Molecular Chaperones / Q000235:genetics; D016366:Open Reading Frames / Q000235:genetics; D010766:Phosphorylation; D014176:Protein Biosynthesis; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D020218:Response Elements / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; C478021:DNAJB9 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; C000619706:HSF1 protein, human; D050956:HSP40 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D051701:Activating Transcription Factor 4