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Vol. 17, Issue 11, 4769-4779, November 2006

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A Novel Function of 14-3-3 Protein: 14-3-3 Is a Heat-Shock–related Molecular Chaperone That Dissolves Thermal-aggregated Proteins

Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Tokushima 770-8503, Japan

Submitted March 23, 2006; Revised July 5, 2006; Accepted August 18, 2006
Monitoring Editor: Jonathan Weissman

The 14-3-3 proteins are highly conserved molecules that function as intracellular adaptors in a variety of biological processes, such as signal transduction, cell cycle control, and apoptosis. Here, we show that a 14-3-3 protein is a heat-shock protein (Hsp) that protects cells against physiological stress as its new cellular function. We have observed that, in Drosophila cells, the 14-3-3 is up-regulated under heat stress conditions, a process mediated by a heat shock transcription factor. As the biological action linked to heat stress, 14-3-3 interacted with apocytochrome c, a mitochondrial precursor protein of cytochrome c, in heat-treated cells, and the suppression of 14-3-3 expression by RNA interference resulted in the formation of significant amounts of aggregated apocytochrome c in the cytosol. The aggregated apocytochrome c was converted to a soluble form by the addition of 14-3-3 protein and ATP in vitro. 14-3-3 also resolubilized heat-aggregated citrate synthase and facilitated its reactivation in cooperation with Hsp70/Hsp40 in vitro. Our observations provide the first direct evidence that a 14-3-3 protein functions as a stress-induced molecular chaperone that dissolves and renaturalizes thermal-aggregated proteins.

Address correspondence to: Hiroshi Kido (kido{at}ier.tokushima-u.ac.jp)

Abbreviations used: ChIP, chromatin immunoprecipitation; CS, citrate synthase; HSE, heat-shock element; HSF, heat-shock transcription factor; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; RNAi, RNA interference