Interferon-β-induced miR-1 alleviates toxic protein accumulation by controlling autophagy

  1. Camilla Nehammer
  2. Patrick Ejlerskov
  3. Sandeep Gopal
  4. Ava Handley
  5. Leelee Ng
  6. Pedro Moreira
  7. Huikyong Lee
  8. Shohreh Issazadeh-Navikas
  9. David C Rubinsztein
  10. Roger Pocock  Is a corresponding author
  1. University of Copenhagen, Denmark
  2. Monash University, Australia
  3. University of Cambridge, United Kingdom

Abstract

Appropriate regulation of autophagy is crucial for clearing toxic proteins from cells. Defective autophagy results in accumulation of toxic protein aggregates that detrimentally affect cellular function and organismal survival. Here, we report that the microRNA miR-1 regulates the autophagy pathway through conserved targeting of the orthologous Tre-2/Bub2/CDC16 (TBC) Rab GTPase-activating proteins TBC-7 and TBC1D15 in Caenorhabditis elegans and mammalian cells, respectively. Loss of miR-1 causes TBC-7/TBC1D15 overexpression, leading to a block on autophagy. Further, we found that the cytokine interferon-b (IFN-b) can induce miR-1 expression in mammalian cells, reducing TBC1D15 levels, and safeguarding against proteotoxic challenges. Therefore, this work provides a potential therapeutic strategy for protein aggregation disorders.

Data availability

RNA sequencing data have been deposited in GEO under accession code GSE128968

The following data sets were generated

Article and author information

Author details

  1. Camilla Nehammer

    Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  2. Patrick Ejlerskov

    Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  3. Sandeep Gopal

    Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Ava Handley

    Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1543-1551
  5. Leelee Ng

    Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Pedro Moreira

    Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Huikyong Lee

    Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Shohreh Issazadeh-Navikas

    Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  9. David C Rubinsztein

    Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5002-5263
  10. Roger Pocock

    Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
    For correspondence
    roger.pocock@monash.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5515-3608

Funding

National Health and Medical Research Council (GNT1137645)

  • Roger Pocock

Lundbeckfonden (R223-2016-849)

  • Shohreh Issazadeh-Navikas

Lundbeckfonden (R210-2015-3372)

  • Patrick Ejlerskov

Wellcome (095317/Z/11/Z)

  • David C Rubinsztein

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

Reviewing Editor

  1. Hitoshi Nakatogawa, Tokyo Institute of Technology, Japan

Version history

  1. Received: July 4, 2019
  2. Accepted: December 3, 2019
  3. Accepted Manuscript published: December 4, 2019 (version 1)
  4. Version of Record published: December 16, 2019 (version 2)

Copyright

© 2019, Nehammer 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

  • 2,722
    Page views
  • 490
    Downloads
  • 16
    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. Camilla Nehammer
  2. Patrick Ejlerskov
  3. Sandeep Gopal
  4. Ava Handley
  5. Leelee Ng
  6. Pedro Moreira
  7. Huikyong Lee
  8. Shohreh Issazadeh-Navikas
  9. David C Rubinsztein
  10. Roger Pocock
(2019)
Interferon-β-induced miR-1 alleviates toxic protein accumulation by controlling autophagy
eLife 8:e49930.
https://doi.org/10.7554/eLife.49930

Share this article

https://doi.org/10.7554/eLife.49930

Further reading

    1. Biochemistry and Chemical Biology
    Jake W Anderson, David Vaisar ... Natalie G Ahn
    Research Article

    Activation of the extracellular signal-regulated kinase-2 (ERK2) by phosphorylation has been shown to involve changes in protein dynamics, as determined by hydrogen-deuterium exchange mass spectrometry (HDX-MS) and NMR relaxation dispersion measurements. These can be described by a global exchange between two conformational states of the active kinase, named ‘L’ and ‘R,’ where R is associated with a catalytically productive ATP-binding mode. An ATP-competitive ERK1/2 inhibitor, Vertex-11e, has properties of conformation selection for the R-state, revealing movements of the activation loop that are allosterically coupled to the kinase active site. However, the features of inhibitors important for R-state selection are unknown. Here, we survey a panel of ATP-competitive ERK inhibitors using HDX-MS and NMR and identify 14 new molecules with properties of R-state selection. They reveal effects propagated to distal regions in the P+1 and helix αF segments surrounding the activation loop, as well as helix αL16. Crystal structures of inhibitor complexes with ERK2 reveal systematic shifts in the Gly loop and helix αC, mediated by a Tyr-Tyr ring stacking interaction and the conserved Lys-Glu salt bridge. The findings suggest a model for the R-state involving small movements in the N-lobe that promote compactness within the kinase active site and alter mobility surrounding the activation loop. Such properties of conformation selection might be exploited to modulate the protein docking interface used by ERK substrates and effectors.

    1. Biochemistry and Chemical Biology
    Anne E Hultgren, Nicole MF Patras, Jenna Hicks
    Feature Article

    Organizations that fund research are keen to ensure that their grant selection processes are fair and equitable for all applicants. In 2020, the Arnold and Mabel Beckman Foundation introduced blinding to the first stage of the process used to review applications for Beckman Young Investigator (BYI) awards: applicants were instructed to blind the technical proposal in their initial Letter of Intent by omitting their name, gender, gender-identifying pronouns, and institutional information. Here we examine the impact of this change by comparing the data on gender and institutional prestige of the applicants in the first four years of the new policy (BYI award years 2021–2024) with data on the last four years of the old policy (2017–2020). We find that under the new policy, the distribution of applicants invited to submit a full application shifted from those affiliated with institutions regarded as more prestigious to those outside of this group, and that this trend continued through to the final program awards. We did not find evidence of a shift in the distribution of applicants with respect to gender.