CRELD1 is an evolutionarily-conserved maturational enhancer of ionotropic acetylcholine receptors

  1. Manuela D'Alessandro
  2. Magali Richard
  3. Christian Stigloher
  4. Vincent Gache
  5. Thomas Boulin
  6. Janet E Richmond
  7. JeanLouis Bessereau  Is a corresponding author
  1. University of Lyon - INSERM - CNRS, France
  2. University of Illinois at Chicago, United States

Abstract

The assembly of neurotransmitter receptors in the endoplasmic reticulum limits the number of receptors delivered to the plasma membrane, ultimately controlling neurotransmitter sensitivity and synaptic transfer function. In a forward genetic screen conducted in the nematode C. elegans, we identified crld-1 as a gene required for the synaptic expression of ionotropic acetylcholine receptors (AChR). We demonstrated that the CRLD-1A isoform is a membrane-associated ER-resident protein disulfide isomerase (PDI). It physically interacts with AChRs and promotes the assembly of AChR subunits in the ER. Mutations of Creld1, the human ortholog of crld-1a, are responsible for developmental cardiac defects. We showed that Creld1 knockdown in mouse muscle cells decreased surface expression of AChRs and that expression of mouse Creld1 in C. elegans rescued crld-1a mutant phenotypes. Altogether these results identify a novel and evolutionarily-conserved maturational enhancer of AChR biogenesis, which controls the abundance of functional receptors at the cell surface.

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. Manuela D'Alessandro

    Institut NeuroMyoGene, University of Lyon - INSERM - CNRS, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Magali Richard

    Institut NeuroMyoGene, University of Lyon - INSERM - CNRS, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Christian Stigloher

    Institut NeuroMyoGene, University of Lyon - INSERM - CNRS, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6941-2669
  4. Vincent Gache

    Institut NeuroMyoGene, University of Lyon - INSERM - CNRS, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Thomas Boulin

    Institut NeuroMyoGene, University of Lyon - INSERM - CNRS, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Janet E Richmond

    Department of Biological Sciences, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. JeanLouis Bessereau

    Institut NeuroMyoGene, University of Lyon - INSERM - CNRS, Lyon, France
    For correspondence
    jean-louis.bessereau@univ-lyon1.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3088-7621

Funding

Association Française contre les Myopathies (Post-doctoral Fellowship 16451)

  • Manuela D'Alessandro

European Molecular Biology Organization (Long term Post-doctoral fellowship)

  • Christian Stigloher

Institut National de la Santé et de la Recherche Médicale (Junior Grant)

  • Thomas Boulin

Association Française contre les Myopathies (Myoneuralp)

  • JeanLouis Bessereau

Deutscher Akademischer Austauschdienst (Postdoctoral Program of the German Academic Exchange Service)

  • Christian Stigloher

Fédération pour la Recherche sur le Cerveau (Operation Espoir en tête 2013)

  • JeanLouis Bessereau

Fondation ARC pour la Recherche sur le Cancer (4th year PhD program 2011)

  • Magali Richard

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

Reviewing Editor

  1. Oliver Hobert, Howard Hughes Medical Institute, Columbia University, United States

Publication history

  1. Received: July 12, 2018
  2. Accepted: November 5, 2018
  3. Accepted Manuscript published: November 8, 2018 (version 1)
  4. Version of Record published: November 20, 2018 (version 2)

Copyright

© 2018, D'Alessandro 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

  • 1,504
    Page views
  • 222
    Downloads
  • 10
    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. Manuela D'Alessandro
  2. Magali Richard
  3. Christian Stigloher
  4. Vincent Gache
  5. Thomas Boulin
  6. Janet E Richmond
  7. JeanLouis Bessereau
(2018)
CRELD1 is an evolutionarily-conserved maturational enhancer of ionotropic acetylcholine receptors
eLife 7:e39649.
https://doi.org/10.7554/eLife.39649

Further reading

    1. Cell Biology
    2. Immunology and Inflammation
    Sara Scinicariello, Adrian Soderholm ... Gijs A Versteeg
    Research Article

    Tristetraprolin (TTP) is a critical negative immune regulator. It binds AU-rich elements in the untranslated-regions of many mRNAs encoding pro-inflammatory mediators, thereby accelerating their decay. A key but poorly understood mechanism of TTP regulation is its timely proteolytic removal: TTP is degraded by the proteasome through yet unidentified phosphorylation-controlled drivers. In this study, we set out to identify factors controlling TTP stability. Cellular assays showed that TTP is strongly lysine-ubiquitinated, which is required for its turnover. A genetic screen identified the ubiquitin E3 ligase HUWE1 as a strong regulator of TTP proteasomal degradation, which we found to control TTP stability indirectly by regulating its phosphorylation. Pharmacological assessment of multiple kinases revealed that HUWE1-regulated TTP phosphorylation and stability was independent of the previously characterized effects of MAPK-mediated S52/S178 phosphorylation. HUWE1 function was dependent on phosphatase and E3 ligase binding sites identified in the TTP C-terminus. Our findings indicate that while phosphorylation of S52/S178 is critical for TTP stabilization at earlier times after pro-inflammatory stimulation, phosphorylation of the TTP C-terminus controls its stability at later stages.

    1. Cell Biology
    Agustin Leonardo Lujan, Ombretta Foresti ... Vivek Malhotra
    Research Article

    We show that TANGO2 in mammalian cells localizes predominantly to mitochondria and partially at mitochondria sites juxtaposed to lipid droplets (LDs) and the endoplasmic reticulum. HepG2 cells and fibroblasts of patients lacking TANGO2 exhibit enlarged LDs. Quantitative lipidomics revealed a marked increase in lysophosphatidic acid (LPA) and a concomitant decrease in its biosynthetic precursor phosphatidic acid (PA). These changes were exacerbated in nutrient-starved cells. Based on our data, we suggest that TANGO2 function is linked to acyl-CoA metabolism, which is necessary for the acylation of LPA to generate PA. The defect in acyl-CoA availability impacts the metabolism of many other fatty acids, generates high levels of reactive oxygen (ROS), and promotes lipid peroxidation. We suggest that the increased size of LDs is a combination of enrichment in peroxidized lipids and a defect in their catabolism. Our findings help explain the physiological consequence of mutations in TANGO2 that induce acute metabolic crises, including rhabdomyolysis, cardiomyopathy, and cardiac arrhythmias, often leading to fatality upon starvation and stress.