RNA-mediated response to heat shock in mammalian cells.
The heat-shock transcription factor 1 (HSF1) has an important role in the heat-shock response in vertebrates by inducing the expression of heat-shock proteins (HSPs) and other cytoprotective proteins. HSF1 is present in unstressed cells in an inactive monomeric form and becomes activated by heat and other stress stimuli. HSF1 activation involves trimerization and acquisition of a site-specific DNA-binding activity, which is negatively regulated by interaction with certain HSPs. Here we show that HSF1 activation by heat shock is an active process that is mediated by a ribonucleoprotein complex containing translation elongation factor eEF1A and a previously unknown non-coding RNA that we term HSR1 (heat shock RNA-1). HSR1 is constitutively expressed in human and rodent cells and its homologues are functionally interchangeable. Both HSR1 and eEF1A are required for HSF1 activation in vitro; antisense oligonucleotides or short interfering (si)RNA against HSR1 impair the heat-shock response in vivo, rendering cells thermosensitive. The central role of HSR1 during heat shock implies that targeting this RNA could serve as a new therapeutic model for cancer, inflammation and other conditions associated with HSF1 deregulation.
Department of Biochemistry, New York University School of Medicine, New York, New York 10016, USA.
Ilya
I
Shamovsky
Maxim
M
Ivannikov
Eugene S
ES
Kandel
David
D
Gershon
Evgeny
E
Nudler
D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004926:Escherichia coli; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000502:physiology*; D006801:Humans; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D020648:Peptide Elongation Factor 1 / Q000378:metabolism; D034622:RNA Interference; D022661:RNA, Untranslated / Q000502:physiology*; D051381:Rats; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; C000619709:Hsf1 protein, rat; D016376:Oligonucleotides, Antisense; D020648:Peptide Elongation Factor 1; D022661:RNA, Untranslated; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors