An inhibitor of HIV-1 protease modulates constitutive eIF2 alpha dephosphorylation to trigger a specific integrated stress response

作者：De Gassart Aude; Bujisic Bojan; Zaffalon Lea; Decosterd Laurent A; Di Micco Antonia; Frera Gianluca; Tallant Remy; Martinon Fabio

来源：Proceedings of the National Academy of Sciences, 2016, 113(2): E117-E126.

DOI：10.1073/pnas.1514076113

• ER stress
• translation initiation
• Nelfinavir
• HIV protease inhibitors
• PPP1R15B

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 a subunit of translation initiation factor 2 (eIF2 alpha) phosphorylation, activating transcription factor-4 (ATF4) induction, and increased expression of known downstream targets. Mechanistically, Nelfinavir-mediated ISR bypassed direct activation of the eIF2 alpha stress kinases and instead relied on the inhibition of the constitutive eIF2 alpha dephosphorylation and down-regulation of the phophatase cofactor CReP (Constitutive Repressor of eIF2 alpha Phosphorylation; also known as PPP1R15B). These findings demonstrate that the modulation of eIF2 alpha-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.

• 出版日期2016-1-12