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Nat Cell Biol. 2018 Aug;20(8):942-953. doi: 10.1038/s41556-018-0141-0. Epub 2018 Jul 16.

IRE1α governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A.

Author information

1
Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.
2
Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile.
3
Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
4
Department of Biology, Faculty of Sciences, University of Chile, Santiago, Chile.
5
Program of Anatomy and Developmental Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
6
Center for Genome Regulation, Faculty of Sciences, University of Chile, Santiago, Chile.
7
Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile.
8
Department of Neuroscience, Faculty of Medicine, University of Chile, Santiago, Chile.
9
Department of Molecular and Integrative Physiology, Division of Metabolism, Endocrinology and Diabetes, The University of Michigan Medical School, Ann Arbor, MI, USA.
10
INSERM U1242 Chemistry, Oncogenesis, Stress and Signaling, University of Rennes 1, Rennes, France.
11
Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France.
12
Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Uchinada, Japan.
13
Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile. chetz@med.uchile.cl.
14
Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile. chetz@med.uchile.cl.
15
Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile. chetz@med.uchile.cl.
16
The Buck Institute for Research in Aging, Novato, CA, USA. chetz@med.uchile.cl.
17
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA. chetz@med.uchile.cl.

Abstract

Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a signalling network known as the unfolded protein response (UPR). Here, we identified filamin A as a major binding partner of the ER stress transducer IRE1α. Filamin A is an actin crosslinking factor involved in cytoskeleton remodelling. We show that IRE1α controls actin cytoskeleton dynamics and affects cell migration upstream of filamin A. The regulation of cytoskeleton dynamics by IRE1α is independent of its canonical role as a UPR mediator, serving instead as a scaffold that recruits and regulates filamin A. Targeting IRE1α expression in mice affected normal brain development, generating a phenotype resembling periventricular heterotopia, a disease linked to the loss of function of filamin A. IRE1α also modulated cell movement and cytoskeleton dynamics in fly and zebrafish models. This study unveils an unanticipated biological function of IRE1α in cell migration, whereby filamin A operates as an interphase between the UPR and the actin cytoskeleton.

PMID:
30013108
DOI:
10.1038/s41556-018-0141-0

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