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Ubiquitin-Conjugating Enzyme UBE2D2 Is Responsible for FBXW2 (F-Box and WD Repeat Domain Containing 2)-Mediated Human GCM1 (Glial Cell Missing Homolog 1) Ubiquitination and Degradation¹

Graduate Institute of Biochemical Sciences,⁴ National Taiwan University, Taipei 106, Taiwan Institute of Biological Chemistry,⁵ Academia Sinica, Taipei 115, Taiwan

ABSTRACT

Glial cell missing homolog 1 (GCM1) is an important transcription factor regulating placental cell fusion. Recently, we have demonstrated that GCM1 is a labile protein and that the F-box protein FBXW2 (F-box and WD repeat domain containing 2) mediates GCM1 ubiquitination for proteasomal degradation. Multiple factors are involved in the ubiquitin-proteasome degradation system. Therefore, in order to better understand the mechanism regulating GCM1 stability, we further isolated and characterized the E2 ubiquitin-conjugating enzyme responsible for FBXW2-mediated ubiquitination of GCM1 in this study. We prepared and screened a variety of E2 proteins in an in vitro ubiquitination assay system for GCM1 and found that UBE2D2 is required for the SCF^FBXW2 E3 ligase in regulation of GCM1 ubiquitination. We also demonstrated that the enzyme activity of UBE2D2 is required for GCMa ubiquitination and for association with the SCF^FBXW2 complex. Moreover, knocking down UBE2D2 expression by RNA interference not only suppressed FBXW2-mediated GCM1 ubiquitination, but also prolonged the half-life of GCM1 in vivo. Our results suggest that UBE2D2 is a functional E2 protein which, together with FBXW2, regulates GCM1 stability in the placenta..

GCM1, pregnancy, placenta, syncytiotrophoblast, trophoblast, ubiquitination

¹Supported by grants to H.C. from the National Science Council of Taiwan (96-2311-B-001-034), National Taiwan University (95R0066-BM06-02), and Academia Sinica of Taiwan.

Correspondence: ²Hungwen Chen, Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan. FAX: 886 2 27889759; e-mail: hwchen{at}gate.sinica.edu.tw

³These authors contributed equally to this work.

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