Inhibiting the integrated stress response pathway prevents aberrant chondrocyte differentiation thereby alleviating chondrodysplasia

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Abstract

The integrated stress response (ISR) is activated by diverse forms of cellular stress, including endoplasmic reticulum (ER) stress, and is associated with diseases. However, the molecular mechanism(s) whereby the ISR impacts on differentiation is incompletely understood. Here, we exploited a mouse model of Metaphyseal Chondrodysplasia type Schmid (MCDS) to provide insight into the impact of the ISR on cell fate. We show the protein kinase RNA-like ER kinase (PERK) pathway that mediates preferential synthesis of ATF4 and CHOP, dominates in causing dysplasia by reverting chondrocyte differentiation via ATF4-directed transactivation of Sox9. Chondrocyte survival is enabled, cell autonomously, by CHOP and dual CHOP-ATF4 transactivation of Fgf21. Treatment of mutant mice with a chemical inhibitor of PERK signaling prevents the differentiation defects and ameliorates chondrodysplasia. By preventing aberrant differentiation, titrated inhibition of the ISR emerges as a rationale therapeutic strategy for stress-induced skeletal disorders.

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Most cited references 85

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Gene Ontology: tool for the unification of biology

Michael Ashburner, Catherine A. Ball, Judith Blake … (2002)

Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.

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DAVID: Database for Annotation, Visualization, and Integrated Discovery.

Glynn Dennis, Brad T. Sherman, Douglas A Hosack … (2003)

Functional annotation of differentially expressed genes is a necessary and critical step in the analysis of microarray data. The distributed nature of biological knowledge frequently requires researchers to navigate through numerous web-accessible databases gathering information one gene at a time. A more judicious approach is to provide query-based access to an integrated database that disseminates biologically rich information across large datasets and displays graphic summaries of functional information. Database for Annotation, Visualization, and Integrated Discovery (DAVID; http://www.david.niaid.nih.gov) addresses this need via four web-based analysis modules: 1) Annotation Tool - rapidly appends descriptive data from several public databases to lists of genes; 2) GoCharts - assigns genes to Gene Ontology functional categories based on user selected classifications and term specificity level; 3) KeggCharts - assigns genes to KEGG metabolic processes and enables users to view genes in the context of biochemical pathway maps; and 4) DomainCharts - groups genes according to PFAM conserved protein domains. Analysis results and graphical displays remain dynamically linked to primary data and external data repositories, thereby furnishing in-depth as well as broad-based data coverage. The functionality provided by DAVID accelerates the analysis of genome-scale datasets by facilitating the transition from data collection to biological meaning.

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The integrated stress response.

Karolina Pakos-Zebrucka, Izabela Koryga, Katarzyna Mnich … (2016)

In response to diverse stress stimuli, eukaryotic cells activate a common adaptive pathway, termed the integrated stress response (ISR), to restore cellular homeostasis. The core event in this pathway is the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) by one of four members of the eIF2α kinase family, which leads to a decrease in global protein synthesis and the induction of selected genes, including the transcription factor ATF4, that together promote cellular recovery. The gene expression program activated by the ISR optimizes the cellular response to stress and is dependent on the cellular context, as well as on the nature and intensity of the stress stimuli. Although the ISR is primarily a pro-survival, homeostatic program, exposure to severe stress can drive signaling toward cell death. Here, we review current understanding of the ISR signaling and how it regulates cell fate under diverse types of stress.

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Author and article information

Contributors

Cheng Wang

Ben Niu

Kwok Yeung Tsang

Andrew Tai

Wilson C W Chan:

ORCID: http://orcid.org/0000-0003-2381-2805

Rebecca L K Lo

Keith K H Leung

Nelson W F Dung

Nobuyuki Itoh

Michael Q Zhang:

ORCID: http://orcid.org/0000-0002-7408-1830

Danny Chan:

ORCID: http://orcid.org/0000-0003-3824-5778

Kathryn Song Eng Cheah:

ORCID: http://orcid.org/0000-0003-0802-8799

Clifford J Rosen: Role: Reviewing Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 19 July 2018

Publication date Collection: 2018

Volume: 7

Electronic Location Identifier: e37673

Affiliations

[1 ]deptSchool of Biomedical Sciences University of Hong Kong Hong KongChina

[2 ]deptGraduate School of Pharmaceutical Sciences University of Kyoto KyotoJapan

[3 ]deptDepartment of Biological Sciences, Center for Systems Biology The University of Texas at Dallas RichardsonUnited States

[4 ]deptMOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology Tsinghua University BeijingChina

[5]Maine Medical Center Research Institute United States

[6]Maine Medical Center Research Institute United States

Author notes

[†]

These authors contributed equally to this work.

Author information

Zhijia Tan https://orcid.org/0000-0003-2295-5169

Wilson C W Chan http://orcid.org/0000-0003-2381-2805

Michael Q Zhang http://orcid.org/0000-0002-7408-1830

Danny Chan http://orcid.org/0000-0003-3824-5778

Kathryn Song Eng Cheah http://orcid.org/0000-0003-0802-8799

Article

Publisher ID: 37673

DOI: 10.7554/eLife.37673

PMC ID: 6053305

PubMed ID: 30024379

SO-VID: 32416627-7c23-451b-81d8-70efeda6aab3

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 18 April 2018

Date accepted : 05 July 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100002920, Research Grants Council, University Grants Committee;

Award ID: AoE/M-04/04

Award Recipient : Kathryn Song Eng Cheah

Funded by: FundRef http://dx.doi.org/10.13039/501100002920, Research Grants Council, University Grants Committee;

Award ID: T12-708/12-N

Award Recipient : Kathryn Song Eng Cheah

Funded by: FundRef http://dx.doi.org/10.13039/501100002920, Research Grants Council, University Grants Committee;

Award ID: N_HKU703/13

Award Recipient : Kathryn Song Eng Cheah

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 31361163004

Award Recipient : Kathryn Song Eng Cheah

Funded by: FundRef http://dx.doi.org/10.13039/501100002920, Research Grants Council, University Grants Committee;

Award ID: HKU 760411M

Award Recipient : Danny Chan

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

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Author impact statement Integrated stress response-induced expression of ATF4 and its transactivation of SOX9 causes aberrant chondrocyte differentiation and skeletal defects which can be alleviated by modulating initiation-factor eIF2α phosphorylation translation control.

ScienceOpen disciplines: Life sciences

Keywords: endoplasmic reticulum stress,integrated stress response,chondrodysplasia,protein kinase rna-like er kinase pathway,atf4,isrib,mouse

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: endoplasmic reticulum stress, integrated stress response, chondrodysplasia, protein kinase rna-like er kinase pathway, atf4, isrib, mouse

Inhibiting the integrated stress response pathway prevents aberrant chondrocyte differentiation thereby alleviating chondrodysplasia

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Stress signalling in stem cells

Most cited references 85

Gene Ontology: tool for the unification of biology

DAVID: Database for Annotation, Visualization, and Integrated Discovery.

The integrated stress response.

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