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J Biol Chem, Vol. 273, Issue 50, 33166-33173, December 11, 1998

Intracellular Proteolytic Cleavage of 9-cis-Retinoic Acid Receptor  by Cathepsin L-type Protease Is a Potential Mechanism for Modulating Thyroid Hormone Action

Takashi Nagaya, Yoshiharu Murata, Shunsuke Yamaguchi, Yoshio Nomura, Sachiko Ohmori, Miyuki Fujieda, Nobuhiko Katunuma, Paul M. Yen^§, William W. Chin^§, and Hisao Seo

From the Department of Endocrinology and Metabolism, Division of Molecular and Cellular Adaptation, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601,  Research Institute of Health, Tokushima Bunri University, Tokushima, Tokushima 770-8514, Japan, and the ^§ Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

We previously reported that the responsiveness of hepatocytes to thyroid hormone is markedly attenuated when they were cultured as monolayers rather than spheroids. To elucidate the mechanisms underlying the altered responsiveness, thyroid hormone receptor auxiliary proteins in the hepatocytes were analyzed by electrophoretic mobility shift assay. The major thyroid hormone receptor auxiliary protein was identified as 9-cis-retinoic acid receptor  (RXR) in the hepatocytes regardless of the culture conditions. The cytoplasmic fraction was shown to contain a protease(s) that cleaves RXR at its amino terminus. The presence of the protease in the cytosol, but not in the nucleus, was ascertained by incubating full-length ³⁵S-labeled RXR with each fraction. Using various protease inhibitors, it was shown that cathepsin L-type protease could participate in the cleavage of the RXR. The enzyme activity was much higher in the monolayers than the spheroids. Inhibition of this enzyme activity in the monolayer hepatocyte resulted in the increase of nuclear RXR protein and the augmentation of T₃-dependent induction of spot 14 mRNA. These results suggest that the changes in cathepsin L-type protease activity in the cytosol may alter the turnover of RXR in the nucleus and modify the function of steroid receptor superfamilies that heterodimerize with RXR.

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