Consecutive interactions with HSP90 and eEF1A underlie a functional maturation and storage pathway of AID in the cytoplasm - Archive ouverte HAL Access content directly
Journal Articles Journal of Experimental Medicine Year : 2015

Consecutive interactions with HSP90 and eEF1A underlie a functional maturation and storage pathway of AID in the cytoplasm

(1, 2, 3) , (1, 4) , (5) , (1) , (2, 3) , (2, 3) , (5, 6) , (7) , (1, 2, 3, 4)
1
2
3
4
5
6
7

Abstract

Activation-induced deaminase (AID) initiates mutagenic pathways to diversify the antibody genes during immune responses. The access of AID to the nucleus is limited by CRM1-mediated nuclear export and by an uncharacterized mechanism of cytoplasmic retention. Here, we define a conformational motif in AID that dictates its cytoplasmic retention and demonstrate that the translation elongation factor eukaryotic elongation factor 1 α (eEF1A) is necessary for AID cytoplasmic sequestering. The mechanism is independent of protein synthesis but dependent on a tRNA-free form of eEF1A. Inhibiting eEF1A prevents the interaction with AID, which accumulates in the nucleus and increases class switch recombination as well as chromosomal translocation byproducts. Most AID is associated to unspecified cytoplasmic complexes. We find that the interactions of AID with eEF1A and heat-shock protein 90 kD (HSP90) are inversely correlated. Despite both interactions stabilizing AID, the nature of the AID fractions associated with HSP90 or eEF1A are different, defining two complexes that sequentially produce and store functional AID in the cytoplasm. In addition, nuclear export and cytoplasmic retention cooperate to exclude AID from the nucleus but might not be functionally equivalent. Our results elucidate the molecular basis of AID cytoplasmic retention, define its functional relevance and distinguish it from other mechanisms regulating AID.
Fichier principal
Vignette du fichier
Methot_2015.pdf (3.65 Mo) Télécharger le fichier
Origin : Publisher files allowed on an open archive
Loading...

Dates and versions

pasteur-02554122 , version 1 (25-04-2020)

Licence

Attribution - NonCommercial - ShareAlike - CC BY 4.0

Identifiers

Cite

Stephen Methot, Ludivine Litzler, Felipe Trajtenberg, Astrid Zahn, Francis Robert, et al.. Consecutive interactions with HSP90 and eEF1A underlie a functional maturation and storage pathway of AID in the cytoplasm. Journal of Experimental Medicine, 2015, 212 (4), pp.581-596. ⟨10.1084/jem.20141157⟩. ⟨pasteur-02554122⟩
22 View
81 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More