An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response.

Details

Ressource 1Download: pnas.201514076.pdf (2351.38 [Ko])
State: Public
Version: Final published version
Serval ID
serval:BIB_C26C4352CC95
Type
Article: article from journal or magazin.
Collection
Publications
Title
An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
De Gassart A., Bujisic B., Zaffalon L., Decosterd L.A., Di Micco A., Frera G., Tallant R., Martinon F.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
2016
Volume
113
Number
2
Pages
E117-E126
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
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.
Keywords
ER stress, translation initiation, Nelfinavir, HIV protease inhibitors, PPP1R15B
Pubmed
Web of science
Open Access
Yes
Create date
08/01/2016 23:07
Last modification date
20/08/2019 16:37
Usage data