IRE1 alpha governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A

Emiliano Molina (1) , Younis M. Hazari (1) , Celia M. Limia (1) , Sebastian Alvarez-Rojas (1) , Ricardo Figueroa (1) , Rene L. Vidal (2, 1) , Diego A. Rodriguez (1) , Claudia A. Rivera (2, 1) , Felipe A. Court (2, 1) , Andres Couve (1) , Ling Qi (3) , Eric Chevet (4, 5) , Ryoko Akai , Takao Iwawaki , Miguel L. Concha (1) , Alvaro Glavic (1) , Christian Gonzalez-Billault (1) , Claudio Hetz (1) , Hery Urra (1) , Daniel R. Henriquez (1) , Jose Canovas (1) , David Villarroel-Campos (1) , Amado Carreras-Sureda (1) , Eduardo Pulgar (1)

1 USACH - Universidad de Santiago de Chile [Santiago]
2 Universidad Mayor
3 University of Michigan [Ann Arbor]
4 COSS - Chemistry, Oncogenesis, Stress and Signaling
5 CRLCC - CRLCC Eugène Marquis

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 IRE1 alpha. Filamin A is an actin crosslinking factor involved in cytoskeleton remodelling. We show that IRE1 alpha controls actin cytoskeleton dynamics and affects cell migration upstream of filamin A. The regulation of cytoskeleton dynamics by IRE1 alpha is independent of its canonical role as a UPR mediator, serving instead as a scaffold that recruits and regulates filamin A. Targeting IRE1 alpha expression in mice affected normal brain development, generating a phenotype resembling periventricular heterotopia, a disease linked to the loss of function of filamin A. IRE1 alpha also modulated cell movement and cytoskeleton dynamics in fly and zebrafish models. This study unveils an unanticipated biological function of IRE1 alpha in cell migration, whereby filamin A operates as an interphase between the UPR and the actin cytoskeleton.

Domains: Life Sciences [q-bio]; Cancer

Emiliano Molina, Younis M. Hazari, Celia M. Limia, Sebastian Alvarez-Rojas, Ricardo Figueroa, et al.. IRE1 alpha governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A. Nature Cell Biology, 2018, 20 (8), pp.942-953. ⟨10.1038/s41556-018-0141-0⟩. ⟨hal-01879956⟩