1. Department of Biochemistry, New York University School of Medicine, New York, New York 10016, USA
2. Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel
3. The Cleveland Clinic Foundation Lerner Research Institute, Cleveland, Ohio 44195, USA
4. Redox Pharmaceutical Corp, Greenvale, New York 11548, USA

Correspondence to: David Gershon^2,4Evgeny Nudler¹ Correspondence and requests for materials should be addressed to E.N. (Email: evgeny.nudler@med.nyu.edu) or D.G. (Email: dgershon@redoxpharm.com).

Abstract

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 proteins¹. 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^{2, 3}, which is negatively regulated by interaction with certain HSPs^{4, 5, 6}. 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.

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