The Translation Initiation Factor 3F (eIF3f) Exhibits a Deubiquitinase Activity Regulating Notch Activation - Institut Pasteur Access content directly
Journal Articles PLoS Biology Year : 2010

The Translation Initiation Factor 3F (eIF3f) Exhibits a Deubiquitinase Activity Regulating Notch Activation

Abstract

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.
Fichier principal
Vignette du fichier
Article_eIF3f.pdf (1.4 Mo) Télécharger le fichier
Origin : Publisher files allowed on an open archive
Loading...

Dates and versions

pasteur-00539184 , version 1 (24-11-2010)

Identifiers

Cite

Julien Moretti, Patricia Chastagner, Stefano Gastaldello, Sara F. Heuss, Annette M. Dirac, et al.. The Translation Initiation Factor 3F (eIF3f) Exhibits a Deubiquitinase Activity Regulating Notch Activation: eIF3f, a DUB in Notch Signaling. PLoS Biology, 2010, 8 (11), pp.e1000545. ⟨10.1371/journal.pbio.1000545⟩. ⟨pasteur-00539184⟩

Collections

PASTEUR CNRS
335 View
335 Download

Altmetric

Share

Gmail Facebook X LinkedIn More