Distinct transcriptional responses elicited by unfolded nuclear or cytoplasmic protein in mammalian cells

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Abstract

Eukaryotic cells possess a variety of signaling pathways that prevent accumulation of unfolded and misfolded proteins. Chief among these is the heat shock response (HSR), which is assumed to respond to unfolded proteins in the cytosol and nucleus alike. Here we probe this axiom further using engineered proteins called 'destabilizing domains', whose folding state we control with a small molecule. The sudden appearance of unfolded protein in mammalian cells elicits a robust transcriptional response, which is distinct from the HSR and other known pathways that respond to unfolded proteins. The cellular response to unfolded protein is strikingly different in the nucleus and the cytosol, although unfolded protein in either compartment engages the p53 network. This response provides cross-protection during subsequent proteotoxic stress, suggesting that it is a central component of protein quality control networks and, like the HSR, is likely to influence the initiation and progression of human pathologies.

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Yusuke Miyazaki

Department of Chemical and Systems Biology, Stanford University, Stanford, United States

Competing interests
The authors declare that no competing interests exist.
Ling-chun Chen

Department of Chemical and Systems Biology, Stanford University, Stanford, United States

Competing interests
The authors declare that no competing interests exist.
Bernard W Chu

Department of Chemical and Systems Biology, Stanford University, Stanford, United States

Competing interests
The authors declare that no competing interests exist.
Tomek Swigut

Department of Chemical and Systems Biology, Stanford University, Stanford, United States

Competing interests
The authors declare that no competing interests exist.
Thomas J Wandless

Department of Chemical and Systems Biology, Stanford University, Stanford, United States

For correspondence
wandless@stanford.edu

Competing interests
The authors declare that no competing interests exist.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.