A secretory pathway kinase regulates sarcoplasmic reticulum Ca2+ homeostasis and protects against heart failure

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Abstract

Ca²⁺ signaling is important for many cellular and physiological processes, including cardiac function. Although sarcoplasmicreticulum (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.

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

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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.
Canzhao Liu

Department of Medicine, University of California, San Diego, La Jolla, United States

Competing interests
The authors declare that no competing interests exist.
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.
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.
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.
Yusu Gu

Department of Medicine, University of California, San Diego, La Jolla, United States

Competing interests
The authors declare that no competing interests exist.
Ju Chen

Department of Medicine, University of California, San Diego, La Jolla, United States

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

"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.

Copyright

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.