Nuclear cytoplasmic shuttling by thyroid hormone receptors - Multiple protein interactions are required for nuclear retention

In this report, we have studied the intracellular dynamics and distribution of the thyroid hormone receptor-beta (TR beta) in living cells, utilizing fusions to the green fluorescent protein. Wild-type TB beta was mostly nuclear in both the absence and presence of triiodothyronine; however, triiodothyronine induced a nuclear reorganization of TR beta. By mutating defined regions of TR beta, we found that both nuclear corepressor and retinoid X receptor are involved in maintaining the unliganded receptor within the nucleus. A TR beta mutant defective in DNA binding had only a slightly altered nuclear/cytoplasmic distribution compared with wild-type TR beta; thus, site-specific DNA binding is not essential for maintaining TR beta within the nucleus. Both AT beta depletion studies and heterokaryon analysis demonstrated that TR beta rapidly shuttles between the nuclear and the cytoplasmic compartments. Cotransfection of nuclear corepressor and retinoid X receptor markedly decreased the shuttling by maintaining unliganded TR beta within the nucleus. In summary, our findings demonstrate that TR beta rapidly shuttles between the nucleus and the cytoplasm and that protein-protein interactions of TR beta with various cofactors, rather than specific DNA interactions, play the predominant role in determining the intracellular distribution of the receptor.