The E3 ligase UBR2 regulates cell death under caspase deficiency via Erk/MAPK pathway |
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Authors: | Elodie Villa,Rachel Paul,Ophé lie Meynet,Sophie Volturo,Guillaume Pinna,Jean-Ehrland Ricci |
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Affiliation: | 1.Université Côte d’Azur, INSERM, C3M Nice, France ;2.Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198 Gif-sur-Yvette, France |
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Abstract: | Escape from cell death is a key event in cancer establishment/progression. While apoptosis is often considered as the main cell death pathway, upon caspase inhibition, cell death is rather delayed than blocked leading to caspase-independent cell death (CICD). Although described for years, CICD’s underlying mechanism remains to be identified. Here, we performed a genome-wide siRNA lethality screening and identified the RING-Type E3 Ubiquitin Transferase (UBR2) as a specific regulator of CICD. Strikingly, UBR2 downregulation sensitized cells towards CICD while its overexpression was protective. We established that UBR2-dependent protection from CICD was mediated by the MAPK/Erk pathway. We then observed that UBR2 is overexpressed in several cancers, especially in breast cancers and contributes to CICD resistance. Therefore, our work defines UBR2 as a novel regulator of CICD, found overexpressed in cancer cells, suggesting that its targeting may represent an innovative way to kill tumor cells.Subject terms: Cancer, Cell death |
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