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Expression Patterns of WSB-1 and USP-33 Underlie Cell-Specific Posttranslational Control of Type 2 Deiodinase in the Rat Brain

Laboratory of Endocrine Neurobiology (C.F., A.Z., G.W., A.K., Z.L., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Tupper Research Institute and Department of Medicine (C.F., P.S., R.M.L.), Division of Endocrinology, Diabetes, and Metabolism, Boston, Massachusetts 02111; Thyroid Section (B.C.G.F., M.A.C., A.C.B.), Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts 02115; and Department of Neuroscience (Z.L.), Faculty of Information Technology, Pázmány Péter Catholic University, Budapest H-1083, Hungary

Address all correspondence and requests for reprints to: Dr. Balázs Gereben, Institute of Experimental Medicine, Laboratory of Endocrine, Neurobiology, Szigony u. 43, Budapest H-1083 Hungary. E-mail: gereben{at}koki.hu; or Dr. Antonio C. Bianco, Brigham and Women’s Hospital at Harvard Institutes of Medicine, Room 643, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115. E-mail: abianco{at}partners.org.

The type 2 deiodinase (D2) activates thyroid hormone and constitutes an important source of 3,5,3',-triiodothyronine in the brain. D2 is inactivated via WSB-1 mediated ubiquitination but can be rescued from proteasomal degradation by USP-33 mediated deubiquitination. Using an in silico analysis of published array data, we found a significant positive correlation between the relative mRNA expression levels of WSB-1 and USP-33 in a set of 56 mouse tissues (r = 0.08; P < 0.04). Subsequently, we used in situ hybridization combined with immunocytochemistry in rat brain to show that in addition to neurons, WSB-1 and USP-33 are differently expressed in astrocytes and tanycytes, the two main D2 expressing cell types in this tissue. Tanycytes, which are thought to participate in the feedback regulation of TRH neurons express both WSB-1 and USP-33, indicating the potential for D2 ubiquitination and deubiquitination in these cells. Notably, only WSB-1 is expressed in glial fibrillary acidic protein-positive astrocytes throughout the brain. Although developmental and environmental signals are known to regulate the expression of WSB-1 and USP-33 in other tissues, our real-time PCR studies indicate that changes in thyroid status do not affect the expression of these genes in several rat brain regions, whereas in the mediobasal hypothalamus, changes in gene expression were minimal. In conclusion, the correlation between the relative mRNA levels of WSB-1 and USP-33 in numerous tissues that do not express D2 suggests that these ubiquitin-related enzymes share additional substrates besides D2. Furthermore, the data indicate that changes in WSB-1 and USP-33 expression are not part of the brain homeostatic response to hypothyroidism or hyperthyroidism.

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