title: 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.
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland;
authors.forename: Aude
authors.initials: A
authors.lastname: De Gassart
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland;
authors.forename: Bojan
authors.initials: B
authors.lastname: Bujisic
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland;
authors.forename: Léa
authors.initials: L
authors.lastname: Zaffalon
authors.affiliation: Laboratory of Clinical Pharmacology, Service of Biomedicine, Lausanne University Hospital, University of Lausanne, Lausanne 1011, Switzerland.
authors.forename: Laurent A
authors.initials: LA
authors.lastname: Decosterd
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland;
authors.forename: Antonia
authors.initials: A
authors.lastname: Di Micco
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland;
authors.forename: Gianluca
authors.initials: G
authors.lastname: Frera
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland;
authors.forename: Rémy
authors.initials: R
authors.lastname: Tallant
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland; fabio.martinon@unil.ch.
authors.forename: Fabio
authors.initials: F
authors.lastname: Martinon
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D019888:Nelfinavir / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D017320:HIV Protease Inhibitors; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051701:Activating Transcription Factor 4; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D054645:Protein Phosphatase 1; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D019888:Nelfinavir
keywords: ER stress; HIV protease inhibitors; Nelfinavir; PPP1R15B; translation initiation