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Importin 13 Regulates Nuclear Import of the Glucocorticoid Receptor in Airway Epithelial Cells

McGill University–Montreal Children's Hospital Research Institute, Montreal; Departments of Human Genetics and Pediatrics, McGill University, Montreal, Quebec; The Hospital for Sick Children Research Institute, University of Toronto, Toronto; The Ottawa Health Research Institute, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

Correspondence and requests for reprints should be addressed to Feige Kaplan, McGill University–Montreal Children's Hospital Research Institute, 4060 St. Catherine St. West, Rm 236, Montreal, PQ, H3Z 2Z3 Canada. E-mail: feige.kaplan{at}mcgill.ca

Antiinflammatory effects of glucocorticoids are critical to treatment of airway inflammation in such common disorders as asthma. There is considerable variation in responsiveness to glucocorticoid, and prolonged exposure can result in glucocorticoid resistance. We cloned LGL2, a glucocorticoid-inducible gene in fetal rat lung. We described the characterization of lgl2 as a nuclear transport protein, classified as importin 13 (IPO13), and demonstrated developmental regulation of IPO13 nucleocytoplasmic shuttling. We now report on the identification of the glucocorticoid receptor (GR) as a cargo substrate for IPO13. Binding of GR and IPO13 was demonstrated by GR-GST pulldown and coimmunoprecipitation. To investigate the role of IPO13 in modulating GR signaling in the lung, we studied IPO13-regulated GR transport in airway epithelial cells. Small interfering RNAs that inhibited IPO13 synthesis prevented nuclear translocation of GR. Silencing of IPO13 also abrogated the ability of cortisol to inhibit synthesis of the inflammatory cytokine IL-8 after stimulation with TNF-. Our findings support a role for IPO13 in promoting nuclear occupancy of GR in a way that strongly potentiates the antiinflammatory effects of glucocorticoids. We speculate that variation in cellular levels of IPO13 and intracellular IPO13 shuttling rates may contribute to glucocorticoid resistance.

Key Words: asthma • gluccorticoid receptor • glucocorticoid responsiveness • importin 13 • nuclear import

CLINICAL RELEVANCE This study identified a glucocorticoid receptor (GR) nuclear transport carrier in the lung. These findings support a role for importin 13 in promoting nuclear entry of GR and may be of relevance to antiinflammatory asthma therapy.

 

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