TY - JOUR TI - The multi-subunit GID/CTLH E3 ubiquitin ligase promotes cell proliferation and targets the transcription factor Hbp1 for degradation AU - Lampert, Fabienne AU - Stafa, Diana AU - Goga, Algera AU - Soste, Martin Varis AU - Gilberto, Samuel AU - Olieric, Natacha AU - Picotti, Paola AU - Stoffel, Markus AU - Peter, Matthias A2 - Dikic, Ivan VL - 7 PY - 2018 DA - 2018/06/18 SP - e35528 C1 - eLife 2018;7:e35528 DO - 10.7554/eLife.35528 UR - https://doi.org/10.7554/eLife.35528 AB - In yeast, the glucose-induced degradation-deficient (GID) E3 ligase selectively degrades superfluous gluconeogenic enzymes. Here, we identified all subunits of the mammalian GID/CTLH complex and provide a comprehensive map of its hierarchical organization and step-wise assembly. Biochemical reconstitution demonstrates that the mammalian complex possesses inherent E3 ubiquitin ligase activity, using Ube2H as its cognate E2. Deletions of multiple GID subunits compromise cell proliferation, and this defect is accompanied by deregulation of critical cell cycle markers such as the retinoblastoma (Rb) tumor suppressor, phospho-Histone H3 and Cyclin A. We identify the negative regulator of pro-proliferative genes Hbp1 as a bonafide GID/CTLH proteolytic substrate. Indeed, Hbp1 accumulates in cells lacking GID/CTLH activity, and Hbp1 physically interacts and is ubiquitinated in vitro by reconstituted GID/CTLH complexes. Our biochemical and cellular analysis thus demonstrates that the GID/CTLH complex prevents cell cycle exit in G1, at least in part by degrading Hbp1. KW - E3 ubiquitin ligase KW - cell proliferation KW - transcription factors KW - metabolism KW - N-end rule JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -