Constitutive nuclear import and stress-regulated nucleocytoplasmic shuttling of mammalian heat-shock factor 1

Milos Vujanac, Angelia Fenaroli, Vincenzo Zimarino

Research output: Contribution to journalArticle

Abstract

Inducible expression of major cytosolic and nuclear chaperone proteins is mediated by the heat-shock transcription factor HSF1 that is activated by derepressive mechanisms triggered by transient heat stress and sustained proteotoxicity. Despite progress in defining essential aspects of HSF1 regulation, little is known about the cellular dynamics enabling this factor to mediate gene responses to cytosolic stress signals. We report that the inactive, stress-responsive form of HSF1 accumulates in the nucleus due to a relatively potent import signal, which can be recognized by importin-α/β, and simultaneously undergoes continuous nucleocytoplasmic shuttling due to a comparatively weak, nonetheless efficient, export activity not involving the classical exportin-1 pathway. Strikingly, experimental stresses at physiological or elevated temperature reversibly inactivate the export competence of HSF1. Likewise, mutations mimicking stress-induced derepression impair export but not import. These findings are consistent with a dynamic process whereby exported molecules that are derepressed in an inductive cytosolic environment are recollected and pause in the nucleoplasm, replacing progressively the inactive pool. While steady-state nuclear distribution of the bulk of HSF1 ensures a rapid gene response to acute heat stress, our results suggest that the capture in the nucleus of molecules primed for activation in the cytosol may underlie responses to sustained proteotoxicity.

Original languageEnglish
Pages (from-to)214-229
Number of pages16
JournalTraffic
Volume6
Issue number3
DOIs
Publication statusPublished - Mar 2005

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Keywords

  • Heat-shock factor 1
  • Mutations
  • Nuclear transport
  • Shuttling
  • Stress

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Genetics
  • Molecular Biology
  • Structural Biology

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