1. Biochemistry and Chemical Biology
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A secretory pathway kinase regulates sarcoplasmic reticulum Ca2+ homeostasis and protects against heart failure

  1. Adam J Pollak
  2. Canzhao Liu
  3. Aparna Gudlur
  4. Joshua E Mayfield
  5. Nancy D Dalton
  6. Yusu Gu
  7. Ju Chen
  8. Joan Heller Brown
  9. Patrick G Hogan
  10. Sandra E Wiley
  11. Kirk L Peterson
  12. Jack E Dixon  Is a corresponding author
  1. University of California, San Diego, United States
  2. La Jolla Institute For Allergy and Immunology, United States
Research Article
  • Cited 12
  • Views 1,338
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Cite this article as: eLife 2018;7:e41378 doi: 10.7554/eLife.41378

Abstract

Ca2+ signaling is important for many cellular and physiological processes, including cardiac function. Although sarcoplasmic reticulum (SR) proteins involved in Ca2+ signaling have been shown to be phosphorylated, the biochemical and physiological roles of protein phosphorylation within the lumen of the SR remain essentially uncharacterized. Our laboratory recently identified an atypical protein kinase, Fam20C, which is uniquely localized to the secretory pathway lumen. Here we show that Fam20C phosphorylates several SR proteins involved in Ca2+ signaling, including calsequestrin2 and Stim1, whose biochemical activities are dramatically regulated by Fam20C mediated phosphorylation. Notably, phosphorylation of Stim1 by Fam20C enhances Stim1 activation and store-operated Ca2+ entry. Physiologically, mice with Fam20c ablated in cardiomyocytes develop heart failure following either aging or induced pressure overload. We extended these observations to show that non-muscle cells lacking Fam20C display altered ER Ca2+ signaling. Overall, we show that Fam20C plays an overarching role in ER/SR Ca2+ homeostasis and cardiac pathophysiology.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Adam J Pollak

    Department of Pharmacology, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Canzhao Liu

    Department of Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Aparna Gudlur

    Division of Signaling and Gene Expression, La Jolla Institute For Allergy and Immunology, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Joshua E Mayfield

    Department of Pharmacology, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Nancy D Dalton

    Department of Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Yusu Gu

    Department of Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ju Chen

    Department of Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Joan Heller Brown

    Department of Pharmacology, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Patrick G Hogan

    Division of Signaling and Gene Expression, La Jolla Institute For Allergy and Immunology, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Sandra E Wiley

    Department of Pharmacology, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Kirk L Peterson

    Department of Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Jack E Dixon

    Department of Pharmacology, University of California, San Diego, La Jolla, United States
    For correspondence
    jedixon@ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8266-5449

Funding

National Institutes of Health (F32HL136122)

  • Adam J Pollak

National Institutes of Health (3T32HL007444-34S1)

  • Adam J Pollak

National Institutes of Health (5T32CA009523-32)

  • Joshua E Mayfield

National Institutes of Health (AI109842)

  • Patrick G Hogan

National Institutes of Health (AI040127)

  • Patrick G Hogan

National Institutes of Health (DK018849-41)

  • Jack E Dixon

National Institutes of Health (DK018024-43)

  • Jack E Dixon

National Institutes of Health (R37HL028143)

  • Joan Heller Brown

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the University of California at San Diego. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University of California at San Diego (Protocol Number: S03039). All surgery was performed under ketamine and xylazine anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. John Kuriyan, University of California, Berkeley, United States

Publication history

  1. Received: August 23, 2018
  2. Accepted: December 3, 2018
  3. Accepted Manuscript published: December 6, 2018 (version 1)
  4. Version of Record published: December 18, 2018 (version 2)
  5. Version of Record updated: December 24, 2018 (version 3)

Copyright

© 2018, Pollak 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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