Thyroid hormone receptor α1 follows a cooperative CRM1/calreticulin-mediated nuclear export pathway

The thyroid hormone receptor alpha 1 (TR alpha) exhibits a dual role as an activator or repressor of its target genes in response to thyroid hormone (T-3) .Previously, we have shown that TR alpha, formerly thought to reside solely in the nucleus bound to DNA, actually shuttles rapidly between the nucleus and cytoplasm. An important aspect of the shuttling activity of TR alpha is its ability to exit the nucleus through the nuclear pore complex. TR alpha export is not sensitive to treatment with the CRM1-specific inhibitor leptomycin B ( LMB) in heterokaryon assays, suggesting a role for an export receptor other than CRM1. Here, we have used a combined approach of in vivo fluorescence recovery after photobleaching experiments, in vitro permeabilized cell nuclear export assays, and glutathione S-transferase pull-down assays to investigate the export pathway used by TR alpha. We show that, in addition to shuttling in heterokaryons, TR alpha shuttles rapidly in an unfused monokaryon system as well. Furthermore, our data show that TR alpha directly interacts with calreticulin, and point to the intriguing possibility that TR alpha follows a cooperative export pathway in which both calreticulin and CRM1 play a role in facilitating efficient translocation of TR alpha from the nucleus to cytoplasm.