The multi-subunit GID/CTLH E3 ligase promotes proliferation and targets the transcription factor Hbp1 for degradation
- ETH Zürich, Switzerland
- Paul Scherrer Institute, Switzerland
Abstract
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files contain the complete lists of mass spectrometry results and SAINT scores
Article and author information
Author details
Funding
Swiss National Science Foundation
- Markus Stoffel
- Matthias Peter
Human Frontier Science Program (LT- 000376/2014-L)
- Fabienne Lampert
European Research Council
- Matthias Peter
ETH Zurich
- Paola Picotti
- Markus Stoffel
- Matthias Peter
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were approved by the Kantonale Veterinäramt Zürich.
Copyright
© 2018, Lampert et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The multi-subunit GID/CTLH E3 ligase promotes proliferation and targets the transcription factor Hbp1 for degradation
eLife 7:e35528.
https://doi.org/10.7554/eLife.35528
