UBTD1 regulates ceramide balance and endolysosomal positioning to coordinate EGFRsignaling

TORRINO, S.; TIROILLE, V.; DOLFI, B.; DUFIES, M.; HINAULT, C.; BONESSO, L.; DAGNINO, S.; UHLER, J. P.; IRONDELLE, M.; GAY, A.-S.; FLEURIOT, L.; Debayle, D.; LACAS-GERVAIS, S.; CORMONT, M.; BERTERO, T.; BOST, F.; GILLERON, J.; CLAVEL, S.

doi:10.1101/2020.05.20.105775

bioRxiv · 10.1101/2020.05.20.105775

UBTD1 regulates ceramide balance and endolysosomal positioning to coordinate EGFRsignaling

TORRINO, S.·TIROILLE, V.·DOLFI, B.·DUFIES, M.·HINAULT, C.·BONESSO, L.·DAGNINO, S.·UHLER, J. P.·IRONDELLE, M.·GAY, A.-S.·FLEURIOT, L.·Debayle, D.·LACAS-GERVAIS, S.·CORMONT, M.·BERTERO, T.·BOST, F.·GILLERON, J.·CLAVEL, S.

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Abstract

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) 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 EGF-driven cell proliferation.

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TORRINO, S., TIROILLE, V., DOLFI, B., DUFIES, M., HINAULT, C., BONESSO, L., DAGNINO, S., UHLER, J. P., IRONDELLE, M., GAY, A.-S., FLEURIOT, L., Debayle, D., LACAS-GERVAIS, S., CORMONT, M., BERTERO, T., BOST, F., GILLERON, J., CLAVEL, S.. 2020-05-20. UBTD1 regulates ceramide balance and endolysosomal positioning to coordinate EGFRsignaling. https://doi.org/10.1101/2020.05.20.105775

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