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

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

SUBMITTER: De Gassart A 

PROVIDER: S-EPMC4720296 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature