The switch-like expression of Heme-regulated kinase 1 mediates neuronal proteostasis following proteasome inhibition

Abstract

We examined the feedback between the major protein degradation pathway, the ubiquitin-proteasome system (UPS), and protein synthesis in rat and mouse neurons. When protein degradation was inhibited, we observed a coordinate dramatic reduction in nascent protein synthesis in neuronal cell bodies and dendrites. The mechanism for translation inhibition involved the phosphorylation of eIF2α, surprisingly mediated by eIF2α kinase 1, or heme-regulated kinase inhibitor (HRI). Under basal conditions, neuronal expression of HRI is barely detectable. Following proteasome inhibition, HRI protein levels increase owing to stabilization of HRI and enhanced translation, likely via the increased availability of tRNAs for its rare codons. Once expressed, HRI is constitutively active in neurons because endogenous heme levels are so low; HRI activity results in eIF2α phosphorylation and the resulting inhibition of translation. These data demonstrate a novel role for HRI in neurons that senses and responds to compromised function of the proteasome to restore proteostasis.

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. Beatriz Alvarez-Castelao

    Max Planck Institute for Brain Research, Frankfurt, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Susanne tom Dieck

    Max Planck Institute for Brain Research, Frankfurt, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Claudia M Fusco

    Max Planck Institute for Brain Research, Frankfurt, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Paul G Donlin-Asp

    Max Planck Institute for Brain Research, Frankfurt, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Julio D Perez

    Max Planck Institute for Brain Research, Frankfurt, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Erin M Schuman

    Max Planck Institute for Brain Research, Frankfurt, Germany
    For correspondence
    erin.schuman@brain.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7053-1005

Funding

Max Planck Society

  • Susanne tom Dieck
  • Claudia M Fusco
  • Paul G Donlin-Asp
  • Julio D Perez
  • Erin M Schuman

European Research Council

  • Erin M Schuman

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

Reviewing Editor

  1. Susan L Ackerman, Howard Hughes Medical Institute, University of California, San Diego, United States

Ethics

Animal experimentation: The housing and sacrificing procedures involving animal treatment and care were conducted in conformity with the institutional guidelines that are in compliance with national and international laws and policies (DIRECTIVE 2010/63/EU; German animal welfare law; FELASA guidelines). The animalswere euthanized according to annex 2 of {section sign} 2 Abs. 2 Tierschutz-Versuchstier-Verordnung. Animal numbers were reported to the local authority (Regierungspräsidium Darmstadt, approval numbers: V54-19c20/15-F126/1020 and V54-19c20/15-F126/1023).

Version history

  1. Received: October 14, 2019
  2. Accepted: April 20, 2020
  3. Accepted Manuscript published: April 24, 2020 (version 1)
  4. Version of Record published: May 14, 2020 (version 2)

Copyright

© 2020, Alvarez-Castelao 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. Beatriz Alvarez-Castelao
  2. Susanne tom Dieck
  3. Claudia M Fusco
  4. Paul G Donlin-Asp
  5. Julio D Perez
  6. Erin M Schuman
(2020)
The switch-like expression of Heme-regulated kinase 1 mediates neuronal proteostasis following proteasome inhibition
eLife 9:e52714.
https://doi.org/10.7554/eLife.52714

Share this article

https://doi.org/10.7554/eLife.52714

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