Abstract for presentation at 11th International Congress of Human Genetics

A role for importin 13, a steroid receptor nuclear import carrier, in steroid response in asthma

  • Dr Feige Kaplan, McGill University- Montreal Children's Hospital Research Institute, Canada
  • Dr Tao Tao, McGill University- Montreal Children's Hospital Research Institute, Canada
  • Jack Lan, McGill University- Montreal Children's Hospital Research Institute, Canada
  • Dr Benjamin Raby, Channing Laboratory, Harvard University, United States
  • Ross Lazarus, Channing Laboratory, Harvard University, United States
  • Dr Scott Weiss, Channing Labotatory, Harvard university, United States

    • Introduction: Anti-inflammatory effects of glucocorticoids (GCs), critical to treatment of airway inflammation in such common disorders as asthma, are dependent on efficient translocation of the GC receptor (GR) from the cytoplasm to the nucleus. There is a considerable variation in responsiveness to glucocorticoid and prolonged exposure can result in GC resistance. We cloned LGL2, a GC-inducible gene in fetal rat lung culture. We described the functional characterization of lgl2 as a nuclear transport protein, currently classified as importin 13 (IPO13). The GC induction and developmental regulation of IPO13 suggested that it may mediate nuclear entry of GR in airway cells thereby influencing steroid responsiveness.
    Objective: Accordingly, our aims were to determine whether IPO13 mediates nuclear entry of GR and to assess association of importin 13 sequence variants with steroid responsiveness in asthma.
    Results: Direct binding of GR and IPO13 was confirmed in vitro by GR-GST pulldown studies and in vivo by coimmunmoprecipitation. Dominant-negative inhibition or RNA silencing of IPO13 led to a 65-70%(p<0.001) reduction in the number of cells in which GR localized to the nucleus. Silencing of IPO13 abrogated the ability of GC to inhibit synthesis of the inflammatory cytokine interleukin-8 in airway epithelial cells. Four IPO13 SNPs associated with the probability of a subject being in the lowest 30% of the cohort with respect to steroid response in adult asthmatics. Nine IPO13 variants impacted on the natural history of airway responsiveness in asthma in the pediatric setting. In this group, the impact of these variants could be abrogated with the use of inhaled corticosteroids.
    Conclusion: Our findings support a role for IPO13 in promoting nuclear occupancy of GR in a way that potentiates anti-inflammatory effects of GC. Association of IPO13 variants with steroid response has relevance to establishment of treatment protocols for asthma.

    Conference Organiser - ICMS Pty Ltd