1. Biochemistry and Chemical Biology
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Distinct transcriptional responses elicited by unfolded nuclear or cytoplasmic protein in mammalian cells

  1. Yusuke Miyazaki
  2. Ling-chun Chen
  3. Bernard W Chu
  4. Tomek Swigut
  5. Thomas J Wandless  Is a corresponding author
  1. Stanford University, United States
Research Article
  • Cited 15
  • Views 2,648
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Cite this article as: eLife 2015;4:e07687 doi: 10.7554/eLife.07687

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.

Article and author information

Author details

  1. Yusuke Miyazaki

    Department of Chemical and Systems Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Ling-chun Chen

    Department of Chemical and Systems Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Bernard W Chu

    Department of Chemical and Systems Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Tomek Swigut

    Department of Chemical and Systems Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. 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.

Reviewing Editor

  1. Ben Cravatt, The Scripps Research Institute, United States

Publication history

  1. Received: March 25, 2015
  2. Accepted: August 13, 2015
  3. Accepted Manuscript published: August 28, 2015 (version 1)
  4. Version of Record published: September 14, 2015 (version 2)

Copyright

© 2015, Miyazaki et al.

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.

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