A secretory pathway kinase regulates sarcoplasmic reticulum Ca2+ homeostasis and protects against heart failure
- University of California, San Diego, United States
- La Jolla Institute For Allergy and Immunology, United States
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
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.
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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A secretory pathway kinase regulates sarcoplasmic reticulum Ca2+ homeostasis and protects against heart failure
eLife 7:e41378.
https://doi.org/10.7554/eLife.41378
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