1. Cell Biology
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Ratiometric sensing of BiP-client versus BiP levels by the unfolded protein response determines its signaling amplitude

  1. Anush Bakunts
  2. Andrea Orsi
  3. Milena Vitale
  4. Angela Cattaneo
  5. Federica Lari
  6. Laura Tadè
  7. Roberto Sitia
  8. Andrea Raimondi
  9. Angela Bachi
  10. Eelco van Anken  Is a corresponding author
  1. San Raffaele Scientific Institute, Italy
  2. FIRC Institute of Molecular Oncology, Italy
Research Article
  • Cited 36
  • Views 2,859
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Cite this article as: eLife 2017;6:e27518 doi: 10.7554/eLife.27518

Abstract

Insufficient folding capacity of the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to restore homeostasis. Yet, how the UPR achieves ER homeostatic readjustment is poorly investigated, since in most studies the ER-stress that is elicited cannot be overcome. Here we show that a proteostatic insult, achieved by persistent expression of the secretory heavy chain of immunoglobulin M (µs), is well-tolerated in HeLa cells. Upon µs expression, its levels temporarily eclipse those of the ER-chaperone BiP, leading to acute, full-geared UPR activation. Once BiP is in excess again, the UPR transitions to chronic, submaximal activation, indicating that the UPR senses ER-stress in a ratiometric fashion. In the process the ER expands about threefold and becomes dominated by BiP. Since the UPR is essential for successful ER homeostatic readjustment in the HeLa-µs model, it provides an ideal system for dissecting the intricacies of how the UPR evaluates and alleviates ER-stress.

Article and author information

Author details

  1. Anush Bakunts

    Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  2. Andrea Orsi

    Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2839-1640
  3. Milena Vitale

    Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7007-402X
  4. Angela Cattaneo

    FIRC Institute of Molecular Oncology, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  5. Federica Lari

    Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  6. Laura Tadè

    Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  7. Roberto Sitia

    Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7086-4152
  8. Andrea Raimondi

    Experimental Imaging Center, San Raffaele Scientific Institute, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  9. Angela Bachi

    Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  10. Eelco van Anken

    Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
    For correspondence
    evananken@mac.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9529-2701

Funding

Giovanni Armenise-Harvard Foundation

  • Eelco van Anken

Ministero della Salute (RF - 2011-02352852)

  • Eelco van Anken

Associazione Italiana per la Ricerca sul Cancro (MFAG 13584)

  • Eelco van Anken

Ministero della Salute (PE-2011-02352286)

  • Roberto Sitia
  • Eelco van Anken

Associazione Italiana per la Ricerca sul Cancro (IG 2016-18824)

  • Roberto Sitia

Fondazione Telethon (GGP15059)

  • Roberto Sitia

Fondazione Cariplo (2015-0591)

  • Roberto Sitia

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Davis Ng, Temasek Life Sciences Laboratory and National University of Singapore, Singapore

Publication history

  1. Received: April 6, 2017
  2. Accepted: December 15, 2017
  3. Accepted Manuscript published: December 18, 2017 (version 1)
  4. Version of Record published: January 31, 2018 (version 2)

Copyright

© 2017, Bakunts 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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