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

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.

Toxoplasma gondiico-opts the unfolded protein response to enhance migration and dissemination of infected host cells

“…As illustrated in a model presented in Fig. 5G , we showed that Toxoplasma infection activates each of the UPR sensor proteins, including IRE1, via ER stress that results at least in part from release of calcium from the organelle, primarily through IP 3 R. In addition to its role in the UPR, IRE1 has recently been shown to have noncanonical functions associated with the remodeling of the cytoskeleton through direct interactions with the actin crosslinking factor filamin A [12]. We showed that Toxoplasma alters the morphology of its host cells through IRE1-filamin A interactions, which directs cytoskeletal remodeling that contributes to a hypermigratory phenotype that facilitated dissemination of the parasite into multiple organs of the infection host.…”

“…Toxoplasma triggers rapid morphological changes in host cells, including disappearance of podosome structures and appearance of lamellipodia [20]. IRE1 has recently been shown to have noncanonical functions in actin cytoskeletal remodeling by directly binding to filamin A [12]. To address whether activation of IRE1 by Toxoplasma infection enhances host cell migration, we quantified the number of lamellipodia per infected cell normalized to uninfected cells (Fig.…”

“…3E) . Furthermore, a truncated c-terminal version of IRE1 ( ire1-Δ965) lacking the proline-rich carboxy-terminal segment of IRE1 that binds filamin A [12] was also impaired in cell migration following infection (Fig. 3E) .…”

“…(A) IRE1 -/- MEF cells were rescued with WT and mutant versions of transient expression IRE1 (green), then cells were fixed and stained using KDEL antibody as an ER marker (red); DAPI was used as to visualize nuclei (blue). Ire1-wt, ire1-kD : kinase domain dead, ire1-eD : endoribonuclease dead, ire1-oD : ire1-Δ965 deletion of filamin A binding site [12]. (B) Lysates were prepared from the cells and IRE1, GFP, or actin protein levels were measured by immunoblot analyses using specific antibodies.…”

“…In addition to its role in the UPR, IRE1 was recently shown to modulate cytoskeletal remodeling and cell migration through direct interactions with the actin crosslinking factor filamin A [12]. The role of IRE1 in cytoskeletal remodeling is enhanced by pharmacological induction of ER stress, but occurs independent of IRE1 protein kinase and endoribonuclease activities [12]; rather, IRE1 serves as a scaffolding protein for filamin A to orchestrate changes in cellular motility. This is noteworthy because Toxoplasma stimulates host cell migration, turning its host cell into a “Trojan Horse” that can ferry parasites throughout the body [13].…”