UBTD1 regulates ceramide balance and endolysosomal positioning to coordinate EGFR signaling
To adapt in an ever-changing environment, cells must integrate physical and chemical signals and translate them into biological meaningful information through complex signaling pathways. By combining lipidomic and proteomic approaches with functional analysis, we have shown that UBTD1 (Ubiquitin domain-containing protein 1) plays a crucial role in both the EGFR (Epidermal Growth Factor Receptor) self-phosphorylation and its lysosomal degradation. On the one hand, by modulating the cellular level of ceramides through ASAH1 (N-Acylsphingosine Amidohydrolase 1) ubiquitination, UBTD1 controls the ligand-independent phosphorylation of EGFR. On the other hand, UBTD1, via the ubiquitination of SQSTM1/p62 (Sequestosome 1) by RNF26 and endolysosome positioning, participates in the lysosomal degradation of EGFR. The coordination of these two ubiquitin-dependent processes contributes to the control of the duration of the EGFR signal. Moreover, we showed that UBTD1 depletion exacerbates EGFR signaling and induces cell proliferation emphasizing a hitherto unknown function of UBTD1 in EGFR-driven human cell proliferation.
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided.
Article and author information
Agence Nationale de la Recherche (ANR-15-IDEX-01)
- Stephan Clavel
Agence Nationale de la Recherche (ANR18-CE14-0035-01-GILLERON)
- Jerome Gilleron
Fondation de France
- Stéphanie Torrino
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Roger J Davis, University of Massachusetts Medical School, United States
- Received: March 12, 2021
- Accepted: April 20, 2021
- Accepted Manuscript published: April 22, 2021 (version 1)
- Version of Record published: May 13, 2021 (version 2)
© 2021, Torrino 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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