An inhibitor of HIV-1 protease modulates constitutive eIF2α 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 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.

Pharmacological eEF 2K activation promotes cell death and inhibits cancer progression

“…To get insight into the mechanisms involved, we treated HeLa cells with 10 lM of NFR and selected and characterized clones that survived and proliferated in the presence of the drug (Fig 1A). NFR concentration can reach up to 17 lM in the plasma of treated patients [25,26] and around 10 lM in liver tissues of mice that receive a dose of NFR reproducing the plasma concentration measured in patients [17]. Up to these concentrations of NFR, we can observe a significant increased viability in the resistant clones compared to the parental population ( Fig 1B).…”

AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity

“…We recently showed that concentrations can reach 10 μM in liver tissues of mice treated with an i.p. dose of NFR reproducing the plasma concentration measured in patients (19). We used the same protocol to interrogate NFRmediated inflammation in mice.…”

“…The HIV-protease inhibitors (HIV-PIs), in particular Nelfinavir (NFR), have been proposed to induce cellular stress both in vivo and in vitro (19,20). Beyond their broad use as anti-HIV drugs, these molecules display beneficial HIV-unrelated functions, antimalaria, antituberculosis, and antitumor properties (20).…”

“…Beyond their broad use as anti-HIV drugs, these molecules display beneficial HIV-unrelated functions, antimalaria, antituberculosis, and antitumor properties (20). At the cellular level, the HIV-PIs trigger an atypical ER stress-like transcriptional response that relies mostly on the activation of the integrated stress response (19,21). However, the exact nature of the stress response engaged by these drugs is poorly understood, and its possible contribution to inflammation has not been investigated.…”

Translating the anticancer properties of eEF2K

“…3 In a previous study we showed that NFR targets translation program by inducing the integrated stress response (ISR). 4 This response is driven by the phosphorylation of the translation initiation factor eIF2a to decrease overall translation initiation and increase production of stress factors including the transcription factor ATF4. While the ISR is a key response that modulates cellular homeostasis, this pathway did not affect cellular viability in presence of the HIV-PIs.…”