The CHORD protein CHP-1 regulates EGF receptor trafficking and signaling in C. elegans and human cells

  1. Andrea Haag
  2. Michael Walser
  3. Adrian Henggeler
  4. Alex Hajnal  Is a corresponding author
  1. University of Zürich, Switzerland

Abstract

The intracellular trafficking of growth factor receptors determines the activity of their downstream signaling pathways. Here, we show that he putative HSP-90 co-chaperone CHP-1 acts as a regulator of EGFR trafficking in C. elegans. Loss of chp-1 causes the retention of the EGFR in the ER and decreases MAPK signaling. CHP-1 is specifically required for EGFR trafficking, as the localization of other transmembrane receptors is unaltered in chp-1(lf) mutants, and the inhibition of hsp-90 or other co-chaperones does not affect EGFR localization. The role of the CHP-1 homolog CHORDC1 during EGFR trafficking is conserved in human cells. Analogous to C. elegans, the response of CHORDC1-deficient A431 cells to EGF stimulation is attenuated, the EGFR accumulates in the ER and ERK2 activity decreases. Although CHP-1 has been proposed to act as a co-chaperone for HSP90, our data indicate that CHP-1 plays an HSP90-independent function in controlling EGFR trafficking through the ER.

Data availability

All data are included in the manuscript.

Article and author information

Author details

  1. Andrea Haag

    Molecular Life Science, University of Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  2. Michael Walser

    Molecular Life Science, University of Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3506-4621
  3. Adrian Henggeler

    Molecular Life Science, University of Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Alex Hajnal

    Molecular Life Science, University of Zürich, Zürich, Switzerland
    For correspondence
    alex.hajnal@imls.uzh.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4098-3721

Funding

Swiss National Science Foundation (31003A-166580)

  • Alex Hajnal

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

Copyright

© 2020, Haag 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

  • 1,183
    views
  • 152
    downloads
  • 3
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Andrea Haag
  2. Michael Walser
  3. Adrian Henggeler
  4. Alex Hajnal
(2020)
The CHORD protein CHP-1 regulates EGF receptor trafficking and signaling in C. elegans and human cells
eLife 9:e50986.
https://doi.org/10.7554/eLife.50986

Share this article

https://doi.org/10.7554/eLife.50986

Further reading

    1. Cell Biology
    Kaiqiang Zhao, Zhongjun Zhou
    Insight

    The accumulation of SIRT4 in the nuclei of kidney cells drives kidney fibrosis, so blocking the movement of this protein could be a potential therapeutic strategy against fibrosis.

    1. Cell Biology
    2. Developmental Biology
    Sarah Rubin, Ankit Agrawal ... Elazar Zelzer
    Research Article

    Chondrocyte columns, which are a hallmark of growth plate architecture, play a central role in bone elongation. Columns are formed by clonal expansion following rotation of the division plane, resulting in a stack of cells oriented parallel to the growth direction. In this work, we analyzed hundreds of Confetti multicolor clones in growth plates of mouse embryos using a pipeline comprising 3D imaging and algorithms for morphometric analysis. Surprisingly, analysis of the elevation angles between neighboring pairs of cells revealed that most cells did not display the typical stacking pattern associated with column formation, implying incomplete rotation of the division plane. Morphological analysis revealed that although embryonic clones were elongated, they formed clusters oriented perpendicular to the growth direction. Analysis of growth plates of postnatal mice revealed both complex columns, composed of ordered and disordered cell stacks, and small, disorganized clusters located in the outer edges. Finally, correlation between the temporal dynamics of the ratios between clusters and columns and between bone elongation and expansion suggests that clusters may promote expansion, whereas columns support elongation. Overall, our findings support the idea that modulations of division plane rotation of proliferating chondrocytes determines the formation of either clusters or columns, a multifunctional design that regulates morphogenesis throughout pre- and postnatal bone growth. Broadly, this work provides a new understanding of the cellular mechanisms underlying growth plate activity and bone elongation during development.