1. Biochemistry and Chemical Biology

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
https://doi.org/10.7554/eLife.41378
Share this article
Cite this article
  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
(2018)
A secretory pathway kinase regulates sarcoplasmic reticulum Ca2+ homeostasis and protects against heart failure
eLife 7:e41378.
https://doi.org/10.7554/eLife.41378
  2. Download BibTeX
  3. Download .RIS

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.

Reviewing Editor

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

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.

Version 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.

Metrics

  • 1,640
    Page views
  • 304
    Downloads
  • 20
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2018)
A secretory pathway kinase regulates sarcoplasmic reticulum Ca2+ homeostasis and protects against heart failure
eLife 7:e41378.
https://doi.org/10.7554/eLife.41378

Share this article

https://doi.org/10.7554/eLife.41378

Categories and tags

Research organism

Further reading

    1. Biochemistry and Chemical Biology
    2. Plant Biology

    Guanidine production by plant homoarginine-6-hydroxylases

    Dietmar Funck, Malte Sinn ... Jörg S Hartig
    Research Article

    Metabolism and biological functions of the nitrogen-rich compound guanidine have long been neglected. The discovery of four classes of guanidine-sensing riboswitches and two pathways for guanidine degradation in bacteria hint at widespread sources of unconjugated guanidine in nature. So far, only three enzymes from a narrow range of bacteria and fungi have been shown to produce guanidine, with the ethylene-forming enzyme (EFE) as the most prominent example. Here, we show that a related class of Fe2+- and 2-oxoglutarate-dependent dioxygenases (2-ODD-C23) highly conserved among plants and algae catalyze the hydroxylation of homoarginine at the C6-position. Spontaneous decay of 6-hydroxyhomoarginine yields guanidine and 2-aminoadipate-6-semialdehyde. The latter can be reduced to pipecolate by pyrroline-5-carboxylate reductase but more likely is oxidized to aminoadipate by aldehyde dehydrogenase ALDH7B in vivo. Arabidopsis has three 2-ODD-C23 isoforms, among which Din11 is unusual because it also accepted arginine as substrate, which was not the case for the other 2-ODD-C23 isoforms from Arabidopsis or other plants. In contrast to EFE, none of the three Arabidopsis enzymes produced ethylene. Guanidine contents were typically between 10 and 20 nmol*(g fresh weight)-1 in Arabidopsis but increased to 100 or 300 nmol*(g fresh weight)-1 after homoarginine feeding or treatment with Din11-inducing methyljasmonate, respectively. In 2-ODD-C23 triple mutants, the guanidine content was strongly reduced, whereas it increased in overexpression plants. We discuss the implications of the finding of widespread guanidine-producing enzymes in photosynthetic eukaryotes as a so far underestimated branch of the bio-geochemical nitrogen cycle and propose possible functions of natural guanidine production.

    1. Biochemistry and Chemical Biology
    2. Medicine

    Bone canonical Wnt signaling is downregulated in type 2 diabetes and associates with higher advanced glycation end-products (AGEs) content and reduced bone strength

    Giulia Leanza, Francesca Cannata ... Nicola Napoli
    Research Article

    Type 2 diabetes (T2D) is associated with higher fracture risk, despite normal or high bone mineral density. We reported that bone formation genes (SOST and RUNX2) and advanced glycation end-products (AGEs) were impaired in T2D. We investigated Wnt signaling regulation and its association with AGEs accumulation and bone strength in T2D from bone tissue of 15 T2D and 21 non-diabetic postmenopausal women undergoing hip arthroplasty. Bone histomorphometry revealed a trend of low mineralized volume in T2D (T2D 0.249% [0.156–0.366]) vs non-diabetic subjects 0.352% [0.269–0.454]; p=0.053, as well as reduced bone strength (T2D 21.60 MPa [13.46–30.10] vs non-diabetic subjects 76.24 MPa [26.81–132.9]; p=0.002). We also showed that gene expression of Wnt agonists LEF-1 (p=0.0136) and WNT10B (p=0.0302) were lower in T2D. Conversely, gene expression of WNT5A (p=0.0232), SOST (p<0.0001), and GSK3B (p=0.0456) were higher, while collagen (COL1A1) was lower in T2D (p=0.0482). AGEs content was associated with SOST and WNT5A (r=0.9231, p<0.0001; r=0.6751, p=0.0322), but inversely correlated with LEF-1 and COL1A1 (r=–0.7500, p=0.0255; r=–0.9762, p=0.0004). SOST was associated with glycemic control and disease duration (r=0.4846, p=0.0043; r=0.7107, p=0.00174), whereas WNT5A and GSK3B were only correlated with glycemic control (r=0.5589, p=0.0037; r=0.4901, p=0.0051). Finally, Young’s modulus was negatively correlated with SOST (r=−0.5675, p=0.0011), AXIN2 (r=−0.5523, p=0.0042), and SFRP5 (r=−0.4442, p=0.0437), while positively correlated with LEF-1 (r=0.4116, p=0.0295) and WNT10B (r=0.6697, p=0.0001). These findings suggest that Wnt signaling and AGEs could be the main determinants of bone fragility in T2D.

    1. Biochemistry and Chemical Biology

    The Listeria monocytogenes persistence factor ClpL is a potent stand-alone disaggregase

    Valentin Bohl, Nele Merret Hollmann ... Axel Mogk
    Research Article

    Heat stress can cause cell death by triggering the aggregation of essential proteins. In bacteria, aggregated proteins are rescued by the canonical Hsp70/AAA+ (ClpB) bi-chaperone disaggregase. Man-made, severe stress conditions applied during, e.g., food processing represent a novel threat for bacteria by exceeding the capacity of the Hsp70/ClpB system. Here, we report on the potent autonomous AAA+ disaggregase ClpL from Listeria monocytogenes that provides enhanced heat resistance to the food-borne pathogen enabling persistence in adverse environments. ClpL shows increased thermal stability and enhanced disaggregation power compared to Hsp70/ClpB, enabling it to withstand severe heat stress and to solubilize tight aggregates. ClpL binds to protein aggregates via aromatic residues present in its N-terminal domain (NTD) that adopts a partially folded and dynamic conformation. Target specificity is achieved by simultaneous interactions of multiple NTDs with the aggregate surface. ClpL shows remarkable structural plasticity by forming diverse higher assembly states through interacting ClpL rings. NTDs become largely sequestered upon ClpL ring interactions. Stabilizing ring assemblies by engineered disulfide bonds strongly reduces disaggregation activity, suggesting that they represent storage states.