Repression of ferritin light chain translation by human eIF3

  1. Mia C Pulos-Holmes
  2. Daniel N Srole
  3. Maria G Juarez
  4. Amy S-Y Lee
  5. David Trombley McSwiggen
  6. Nicholas T Ingolia
  7. Jamie H Cate  Is a corresponding author
  1. University of California, Berkeley, United States
  2. Brandeis University, United States

Abstract

A central problem in human biology remains the discovery of causal molecular links between mutations identified in genome-wide association studies (GWAS) and their corresponding disease traits. This challenge is magnified for variants residing in non-coding regions of the genome. Single-nucleotide polymorphisms (SNPs) in the 5ʹ untranslated region (5ʹ-UTR) of the ferritin light chain (FTL) gene that cause hyperferritinemia are reported to disrupt translation repression by altering iron regulatory protein (IRP) interactions with the FTL mRNA 5ʹ-UTR. Here, we show that human eukaryotic translation initiation factor 3 (eIF3) acts as a distinct repressor of FTL mRNA translation, and eIF3-mediated FTL repression is disrupted by a subset of SNPs in FTL that cause hyperferritinemia. These results identify a direct role for eIF3-mediated translational control in a specific human disease.

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. Mia C Pulos-Holmes

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Daniel N Srole

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Maria G Juarez

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Amy S-Y Lee

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. David Trombley McSwiggen

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3844-7433
  6. Nicholas T Ingolia

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3395-1545
  7. Jamie H Cate

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, United States
    For correspondence
    jcate@lbl.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5965-7902

Funding

National Institute of General Medical Sciences (P50 GM102706)

  • Mia C Pulos-Holmes
  • Daniel N Srole
  • Maria G Juarez
  • Amy S-Y Lee
  • David Trombley McSwiggen
  • Nicholas T Ingolia
  • Jamie H Cate

National Institute of General Medical Sciences (R01 GM065050)

  • Mia C Pulos-Holmes
  • Daniel N Srole
  • Maria G Juarez
  • Jamie H Cate

American Heart Association (16PRE30140013)

  • Mia C Pulos-Holmes

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

Reviewing Editor

  1. Alan G Hinnebusch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States

Version history

  1. Received: May 4, 2019
  2. Accepted: August 14, 2019
  3. Accepted Manuscript published: August 15, 2019 (version 1)
  4. Version of Record published: September 3, 2019 (version 2)

Copyright

© 2019, Pulos-Holmes 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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  1. Mia C Pulos-Holmes
  2. Daniel N Srole
  3. Maria G Juarez
  4. Amy S-Y Lee
  5. David Trombley McSwiggen
  6. Nicholas T Ingolia
  7. Jamie H Cate
(2019)
Repression of ferritin light chain translation by human eIF3
eLife 8:e48193.
https://doi.org/10.7554/eLife.48193

Share this article

https://doi.org/10.7554/eLife.48193

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