ArticleProceedings of the National Academy of Sciences of the United States of America2016
An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 64 citations in OpenAlex.
- Impact of proteostasis workload on sensitivity to proteasome inhibitors in multiple myeloma.Clinical and experimental medicine · 2025Review
- Harnessing p53 for targeted cancer therapy: new advances and future directions.Transcription · 2025Review
- Emerging Molecular-Genetic Families in Dystonia: Endosome-Autophagosome-Lysosome and Integrated Stress Response Pathways.Movement disorders : official journal of the Movement Disorder Society · 2025Review
- Targeting apoptotic pathways for cancer therapy.The Journal of clinical investigation · 2024Review
- Mammalian integrated stress responses in stressed organelles and their functions.Acta pharmacologica Sinica · 2024Review
- Nelfinavir inhibition of Kaposi's sarcoma-associated herpesvirus protein expression and capsid assembly.Infectious agents and cancer · 2024Article
- ATF4 Signaling in HIV-1 Infection: Viral Subversion of a Stress Response Transcription Factor.Biology · 2024Review
- Nelfinavir Inhibition of Kaposi's sarcoma-associated herpesvirus protein expression and capsid assembly.Research square · 2023Article
- The transcription regulator ATF4 is a mediator of skeletal muscle aging.GeroScience · 2023Article
- Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors.International journal of molecular sciences · 2023Review
- Article
- The integrated stress response in cancer progression: a force for plasticity and resistance.Frontiers in oncology · 2023Review
- DYT-TOR1A genotype alters extracellular vesicle composition in murine cell model and shows potential for biomarker discovery.Dystonia (Lausanne, Switzerland) · 2023Article
- PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the Integrated Stress Response.Nature communications · 2022Article
- Targeting the integrated stress response in hematologic malignancies.Experimental hematology & oncology · 2022Review
- The aspartyl protease DDI2 drives adaptation to proteasome inhibition in multiple myeloma.Cell death & disease · 2022Article
- The integrated stress response in ischemic diseases.Cell death and differentiation · 2022Review
- Functionally distinct roles for eEF2K in the control of ribosome availability and p-body abundance.Nature communications · 2021Article
- Treatment with HIV-Protease Inhibitor Nelfinavir Identifies Membrane Lipid Composition and Fluidity as a Therapeutic Target in Advanced Multiple Myeloma.Cancer research · 2021Article
- Salubrinal Enhances Cancer Cell Death during Glucose Deprivation through the Upregulation of xCT and Mitochondrial Oxidative Stress.Biomedicines · 2021Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.