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

• Published in: Nature cell biology Vol. 20; no. 8; pp. 942 - 953
• Main Authors: Urra, Hery, Henriquez, Daniel R., Cánovas, José, Villarroel-Campos, David, Carreras-Sureda, Amado, Pulgar, Eduardo, Molina, Emiliano, Hazari, Younis M., Limia, Celia M., Alvarez-Rojas, Sebastián, Figueroa, Ricardo, Vidal, Rene L., Rodriguez, Diego A., Rivera, Claudia A., Court, Felipe A., Couve, Andrés, Qi, Ling, Chevet, Eric, Akai, Ryoko, Iwawaki, Takao, Concha, Miguel L., Glavic, Álvaro, Gonzalez-Billault, Christian, Hetz, Claudio
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2018; Nature Publishing Group
• Subjects: 13/89; 13/95; 14/1; 14/19; 14/28; 38/70; 42/35; 42/47; 45/77; 631/80/128/1276; 631/80/313/1463; 631/80/470; 631/80/84; 96/95; Actin; Actin Cytoskeleton - metabolism; Animal models; Animals; Brain; Cancer; Cancer Research; Cell adhesion & migration; Cell Biology; Cell migration; Cell Movement; Crosslinking; Cytoskeleton; Developmental Biology; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Endoplasmic reticulum; Endoribonucleases - deficiency; Endoribonucleases - genetics; Endoribonucleases - metabolism; Evolution, Molecular; Female; Fibroblasts - metabolism; Filamins - genetics; Filamins - metabolism; HEK293 Cells; Humans; Kinetics; Life Sciences; Male; Mice; Mice, Knockout; Neurons - metabolism; Neurons - pathology; Periventricular Nodular Heterotopia - genetics; Periventricular Nodular Heterotopia - metabolism; Periventricular Nodular Heterotopia - pathology; Phenotypes; Phosphorylation; Protein Binding; Protein folding; Protein Interaction Domains and Motifs; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins; Signal Transduction; Stem Cells; Unfolded Protein Response; Zebrafish; Zebrafish - genetics; Zebrafish - metabolism; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-018-0141-0

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. Urra et al. discover that IRE1α, an ER stress mediator, interacts with filamin A and controls actin dynamics and cell migration in mouse, Drosophila and zebrafish models in a manner independent of its canonical function.