Editors' ChoiceCell Biology

Making cells move with IRE1α

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Sci. Signal.  28 Aug 2018:
Vol. 11, Issue 545, eaav1986
DOI: 10.1126/scisignal.aav1986

IRE1α promotes cell migration independently of its function as a transducer of ER stress responses.

Endoplasmic reticulum (ER) stress triggers responses by three different transducers, one of which is IRE1α, a protein with kinase and endonuclease activities. Urra et al. identified the actin-crosslinking protein filamin A as a binding partner for IRE1α. Cells deficient in IRE1α showed defects in migration that depended on filamin A. Phosphorylation of filamin A at Ser2152 enhances its ability to remodel the cytoskeleton, and IRE1α promoted the phosphorylation of this site by PKCα. This effect was independent of factors required for IRE1α to mediate ER stress responses, including its endonuclease activity, its kinase activity, or the transcription factor XBP1, its downstream effector in ER stress responses. Instead, dimerization was required for IRE1α to promote the phosphorylation of filamin A and cell migration. The role of IRE1α in cell migration was evolutionarily conserved because knockdown of IRE1α impaired hemocyte migration in Drosophila and morphogenetic cell movements in developing zebrafish embryos. Mutations in FLNA cause periventricular nodular heterotopia, a condition in which neurons do not properly migrate from the ventricles, resulting in malformation of cortical development. Mice with genetic ablation of IRE1α had reduced cortical thickness, a phenotype that is consistent with defective neuronal migration. Similarly, mice subjected to knockdown of IRE1α in utero showed decreased neuronal migration, and this defect was rescued by expression of wild-type filamin A, but not the nonphosphorylatable S2152A mutant. These results demonstrate that IRE1α has a role in cell migration that is mediated by its interaction with filamin A and that this role is independent of its function as a transducer of ER stress responses.

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