An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response.
Détails
Télécharger: pnas.201514076.pdf (2351.38 [Ko])
Etat: Public
Version: Final published version
Etat: Public
Version: Final published version
ID Serval
serval:BIB_C26C4352CC95
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response.
Périodique
Proceedings of the National Academy of Sciences of the United States of America
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Statut éditorial
Publié
Date de publication
2016
Volume
113
Numéro
2
Pages
E117-E126
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
Inhibitors of the HIV aspartyl protease [HIV protease inhibitors (HIV-PIs)] are the cornerstone of treatment for HIV. Beyond their well-defined antiretroviral activity, these drugs have additional effects that modulate cell viability and homeostasis. However, little is known about the virus-independent pathways engaged by these molecules. Here we show that the HIV-PI Nelfinavir decreases translation rates and promotes a transcriptional program characteristic of the integrated stress response (ISR). Mice treated with Nelfinavir display hallmarks of this stress response in the liver, including α subunit of translation initiation factor 2 (eIF2α) phosphorylation, activating transcription factor-4 (ATF4) induction, and increased expression of known downstream targets. Mechanistically, Nelfinavir-mediated ISR bypassed direct activation of the eIF2α stress kinases and instead relied on the inhibition of the constitutive eIF2α dephosphorylation and down-regulation of the phophatase cofactor CReP (Constitutive Repressor of eIF2α Phosphorylation; also known as PPP1R15B). These findings demonstrate that the modulation of eIF2α-specific phosphatase cofactor activity can be a rheostat of cellular homeostasis that initiates a functional ISR and suggest that the HIV-PIs could be repositioned as therapeutics in human diseases to modulate translation rates and stress responses.
Mots-clé
ER stress, translation initiation, Nelfinavir, HIV protease inhibitors, PPP1R15B
Pubmed
Web of science
Open Access
Oui
Création de la notice
08/01/2016 23:07
Dernière modification de la notice
20/08/2019 16:37