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Specific Ubiquitin-Conjugating Enzymes Promote Degradation of Specific Nuclear Receptor Coactivators

Department of Surgery, Medical Microbiology, and Immunology and Cancer Center Criss II (F.Y., X.G., Z.N.), Creighton University, Omaha, Nebraska 68178; and Department of Molecular and Cellular Biology (D.M.L.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Zafar Nawaz, Ph.D., Department of Surgery, Medical Microbiology & Immunology and Cancer Center, Criss II, Room 518, Creighton University, 2500 California Plaza, Omaha, Nebraska 68178. E-mail: znawaz{at}creighton.edu.

Nuclear receptor coactivators (NRCoAs) are nuclear hormone receptor-associated regulatory proteins that interact with members of the nuclear receptor superfamily in the presence of their cognate ligand, enhancing their transcriptional activity. The identification of ubiquitin-proteasome pathway proteins as coactivators provides evidence that ubiquitin-proteasome-mediated protein degradation plays an integral role in eukaryotic gene transcription. It has also been observed that nuclear receptors themselves are ubiquitinated and degraded in a hormone-dependent manner and that ubiquitin-proteasome function is essential for most nuclear receptors to function as transactivators. Here, we show that specific ubiquitin-proteasome pathway enzymes target specific NRCoA proteins in vivo and in vitro. First, using a temperature-sensitive cell line that contains a thermolabile ubiquitin-activating E1 enzyme, we confirmed that NRCoA proteins are targets of the ubiquitin-proteasome pathway. Then using coimmunoprecipitation studies, we also demonstrate that in vivo, NRCoA proteins are ubiquitinated. Finally, we illustrate that in vitro, NRCoA ubiquitination and degradation depend on the ubiquitin-activating enzyme (E1) and on specific ubiquitin-conjugating enzymes (E2) for each of the coactivators.

NURSA Molecule Pages Link:

Coregulators:   E6AP  |  UBCH7  |  CBP  |  SRC-1  |  GRIP1  |  AIB1

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