Multiple exportins influence thyroid hormone receptor localization.

The thyroid hormone receptor (TR) undergoes nucleocytoplasmic shuttling and regulates target genes involved in metabolism and development. Previously， we showed that TR follows a CRM1/calreticulin-mediated nuclear export pathway. However， two lines of evidence suggest TR also follows another pathway: export is only partially blocked by leptomycin B (LMB)， a CRM1-specific inhibitor; and we identified nuclear export signals in TR that are LMB-resistant. To determine whether other exportins are involved in TR shuttling， we used RNA interference and fluorescence recovery after photobleaching shuttling assays in transfected cells. Knockdown of exportins 4， 5， and 7 altered TR shuttling dynamics， and when exportins 5 and 7 were overexpressed， TR distribution shifted toward the cytosol. To further assess the effects of exportin overexpression， we examined transactivation of a TR-responsive reporter gene. Our data indicate that multiple exportins influence TR localization， highlighting a fine balance of nuclear import， retention， and export that modulates TR function.