In the version of this Article originally published, the competing interests statement was missing. The authors declare no competing interests; this statement has now been added in all online versions of the Article.
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.
Actin Cytoskeleton/metabolism , Cell Movement , Endoribonucleases/metabolism , Fibroblasts/metabolism , Filamins/metabolism , Neurons/metabolism , Protein Serine-Threonine Kinases/metabolism , Animals , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Endoribonucleases/deficiency , Endoribonucleases/genetics , Evolution, Molecular , Female , Filamins/genetics , HEK293 Cells , Humans , Kinetics , Male , Mice , Mice, Knockout , Neurons/pathology , Periventricular Nodular Heterotopia/genetics , Periventricular Nodular Heterotopia/metabolism , Periventricular Nodular Heterotopia/pathology , Phosphorylation , Protein Binding , Protein Interaction Domains and Motifs , Protein Serine-Threonine Kinases/deficiency , Protein Serine-Threonine Kinases/genetics , Signal Transduction , Unfolded Protein Response , Zebrafish/genetics , Zebrafish/metabolism , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolism
PURPOSE: Different mutations in coding and non-coding sequences of the SERPINA1 gene have been implicated in the pathogenesis of COPD. However, - 10T/C mutation in the hepatocyte-directed promoter region has not been associated with COPD pathogenesis so far. Here, we report an increased frequency of - 10C genotype that is associated with decreased levels of serum alpha1-antitrypsin (α1AT) in COPD patients. METHODS: The quantification of serum α1AT was done by ELISA, the phenol-chloroform method was used for DNA extraction, PCR products were directly sequenced. The IBM SPSS Statistics v21 software was used for statistical analyses of the data. RESULTS: The mean serum α1AT level was found to be 1.203+0.239 and 3.162+0.160 g/L in COPD cases and in control, respectively. The - 10C allele is associated with an increased risk of COPD [OR, 3.50 (95%CI, 1.86-6.58); p < 0.001]. The combined variant genotype (TT+CC) was significantly found associated with an increased risk of COPD [OR, 3.20 (95% CI, 1.47-6.96); p = 0.003]. A significant association of the family history with COPD (overall p value= 0.0331) suggests that genetics may play an important role in the pathogenesis of COPD. CONCLUSION: The polymorphism associated with hepatocyte-specific promoter region (- 10T/C) is likely to be associated with the pathogenesis of COPD. It is quite possible that the change of the base in the hepatocyte-specific promoter of the SERPINA1 gene can modulate its strength, thereby driving the reduced expression of α1AT.
Hepatocytes/enzymology , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Pulmonary Disease, Chronic Obstructive/genetics , alpha 1-Antitrypsin/genetics , Case-Control Studies , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Humans , India/epidemiology , Male , Phenotype , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/enzymology , Pulmonary Disease, Chronic Obstructive/ethnology , Risk Factors , alpha 1-Antitrypsin/blood
