title: Multiple novel signals mediate thyroid hormone receptor nuclear import and export.
abstract: Thyroid hormone receptor (TR) is a member of the nuclear receptor superfamily that shuttles between the cytosol and nucleus. The fine balance between nuclear import and export of TR has emerged as a critical control point for modulating thyroid hormone-responsive gene expression; however, sequence motifs of TR that mediate shuttling are not fully defined. Here, we characterized multiple signals that direct TR shuttling. Along with the known nuclear localization signal in the hinge domain, we identified a novel nuclear localization signal in the A/B domain of thyroid hormone receptor α1 that is absent in thyroid hormone receptor β1 and inactive in the oncoprotein v-ErbA. Our prior studies showed that thyroid hormone receptor α1 exits the nucleus through two pathways, one dependent on the export factor CRM1 and the other CRM1-independent. Here, we identified three novel CRM1-independent nuclear export signal (NES) motifs in the ligand-binding domain as follows: a highly conserved NES in helix 12 (NES-H12) and two additional NES sequences spanning helix 3 and helix 6, respectively. Mutations predicted to disrupt the α-helical structure resulted in a significant decrease in NES-H12 activity. The high degree of conservation of helix 12 suggests that this region may function as a key NES in other nuclear receptors. Furthermore, our mutagenesis studies on NES-H12 suggest that altered shuttling of thyroid hormone receptor β1 may be a contributing factor in resistance to thyroid hormone syndrome. Taken together, our findings provide a detailed mechanistic understanding of the multiple signals that work together to regulate TR shuttling and transcriptional activity, and they provide important insights into nuclear receptor function in general.
authors: Department of Biology, College of William and Mary, Williamsburg, Virginia 23187, USA.
authors: Manohara S
authors: MS
authors: Mavinakere
authors: Jeremy M
authors: JM
authors: Powers
authors: Kelly S
authors: KS
authors: Subramanian
authors: Vincent R
authors: VR
authors: Roggero
authors: Lizabeth A
authors: LA
authors: Allison
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D020816:Amino Acid Motifs; D000818:Animals; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism*; D018774:Oncogene Proteins v-erbA / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D019913:Nuclear Localization Signals; D018774:Oncogene Proteins v-erbA; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta