The translation initiation factor 3f (eIF3f) exhibits a deubiquitinase activity regulating Notch activation.

Activation of the mammalian Notch receptor after ligand binding relies on a succession of events including metalloprotease-cleavage, endocytosis, monoubiquitination, and eventually processing by the gamma-secretase, giving rise to a soluble, transcriptionally active molecule. The Notch1 receptor was...

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Autores principales:	Julien Moretti, Patricia Chastagner, Stefano Gastaldello, Sara F Heuss, Annette M Dirac, René Bernards, Maria G Masucci, Alain Israël, Christel Brou
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/6aa96086ccfc4d12b2531f28cfae9c01
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spelling	oai:doaj.org-article:6aa96086ccfc4d12b2531f28cfae9c012021-11-18T05:36:56ZThe translation initiation factor 3f (eIF3f) exhibits a deubiquitinase activity regulating Notch activation.1544-91731545-788510.1371/journal.pbio.1000545https://doaj.org/article/6aa96086ccfc4d12b2531f28cfae9c012010-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21124883/pdf/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Activation of the mammalian Notch receptor after ligand binding relies on a succession of events including metalloprotease-cleavage, endocytosis, monoubiquitination, and eventually processing by the gamma-secretase, giving rise to a soluble, transcriptionally active molecule. The Notch1 receptor was proposed to be monoubiquitinated before its gamma-secretase cleavage; the targeted lysine has been localized to its submembrane domain. Investigating how this step might be regulated by a deubiquitinase (DUB) activity will provide new insight for understanding Notch receptor activation and downstream signaling. An immunofluorescence-based screening of an shRNA library allowed us to identify eIF3f, previously known as one of the subunits of the translation initiation factor eIF3, as a DUB targeting the activated Notch receptor. We show that eIF3f has an intrinsic DUB activity. Knocking down eIF3f leads to an accumulation of monoubiquitinated forms of activated Notch, an effect counteracted by murine WT eIF3f but not by a catalytically inactive mutant. We also show that eIF3f is recruited to activated Notch on endocytic vesicles by the putative E3 ubiquitin ligase Deltex1, which serves as a bridging factor. Finally, catalytically inactive forms of eIF3f as well as shRNAs targeting eIF3f repress Notch activation in a coculture assay, showing that eIF3f is a new positive regulator of the Notch pathway. Our results support two new and provocative conclusions: (1) The activated form of Notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. (2) The enzyme accounting for this deubiquitinase activity is eIF3f, known so far as a translation initiation factor. These data improve our knowledge of Notch signaling but also open new avenues of research on the Zomes family and the translation initiation factors.Julien MorettiPatricia ChastagnerStefano GastaldelloSara F HeussAnnette M DiracRené BernardsMaria G MasucciAlain IsraëlChristel BrouPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 8, Iss 11, p e1000545 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Julien Moretti Patricia Chastagner Stefano Gastaldello Sara F Heuss Annette M Dirac René Bernards Maria G Masucci Alain Israël Christel Brou The translation initiation factor 3f (eIF3f) exhibits a deubiquitinase activity regulating Notch activation.
description	Activation of the mammalian Notch receptor after ligand binding relies on a succession of events including metalloprotease-cleavage, endocytosis, monoubiquitination, and eventually processing by the gamma-secretase, giving rise to a soluble, transcriptionally active molecule. The Notch1 receptor was proposed to be monoubiquitinated before its gamma-secretase cleavage; the targeted lysine has been localized to its submembrane domain. Investigating how this step might be regulated by a deubiquitinase (DUB) activity will provide new insight for understanding Notch receptor activation and downstream signaling. An immunofluorescence-based screening of an shRNA library allowed us to identify eIF3f, previously known as one of the subunits of the translation initiation factor eIF3, as a DUB targeting the activated Notch receptor. We show that eIF3f has an intrinsic DUB activity. Knocking down eIF3f leads to an accumulation of monoubiquitinated forms of activated Notch, an effect counteracted by murine WT eIF3f but not by a catalytically inactive mutant. We also show that eIF3f is recruited to activated Notch on endocytic vesicles by the putative E3 ubiquitin ligase Deltex1, which serves as a bridging factor. Finally, catalytically inactive forms of eIF3f as well as shRNAs targeting eIF3f repress Notch activation in a coculture assay, showing that eIF3f is a new positive regulator of the Notch pathway. Our results support two new and provocative conclusions: (1) The activated form of Notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. (2) The enzyme accounting for this deubiquitinase activity is eIF3f, known so far as a translation initiation factor. These data improve our knowledge of Notch signaling but also open new avenues of research on the Zomes family and the translation initiation factors.
format	article
author	Julien Moretti Patricia Chastagner Stefano Gastaldello Sara F Heuss Annette M Dirac René Bernards Maria G Masucci Alain Israël Christel Brou
author_facet	Julien Moretti Patricia Chastagner Stefano Gastaldello Sara F Heuss Annette M Dirac René Bernards Maria G Masucci Alain Israël Christel Brou
author_sort	Julien Moretti
title	The translation initiation factor 3f (eIF3f) exhibits a deubiquitinase activity regulating Notch activation.
title_short	The translation initiation factor 3f (eIF3f) exhibits a deubiquitinase activity regulating Notch activation.
title_full	The translation initiation factor 3f (eIF3f) exhibits a deubiquitinase activity regulating Notch activation.
title_fullStr	The translation initiation factor 3f (eIF3f) exhibits a deubiquitinase activity regulating Notch activation.
title_full_unstemmed	The translation initiation factor 3f (eIF3f) exhibits a deubiquitinase activity regulating Notch activation.
title_sort	translation initiation factor 3f (eif3f) exhibits a deubiquitinase activity regulating notch activation.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/6aa96086ccfc4d12b2531f28cfae9c01
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The translation initiation factor 3f (eIF3f) exhibits a deubiquitinase activity regulating Notch activation.

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