De Gassart Aude, Bujisic Bojan, Zaffalon Léa, Decosterd Laurent A, Di Micco Antonia, Frera Gianluca, Tallant Rémy, Martinon Fabio
Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland;
Laboratory of Clinical Pharmacology, Service of Biomedicine, Lausanne University Hospital, University of Lausanne, Lausanne 1011, Switzerland.
Proc Natl Acad Sci U S A. 2016 Jan 12;113(2):E117-26. doi: 10.1073/pnas.1514076113. Epub 2015 Dec 29.
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.
HIV天冬氨酸蛋白酶抑制剂[HIV蛋白酶抑制剂（HIV-PIs）]是HIV治疗的基石。除了其明确的抗逆转录病毒活性外，这些药物还有调节细胞活力和体内平衡的额外作用。然而，对于这些分子所涉及的与病毒无关的途径知之甚少。在此我们表明，HIV-PI奈非那韦降低翻译速率并促进整合应激反应（ISR）特有的转录程序。用奈非那韦治疗的小鼠在肝脏中表现出这种应激反应的特征，包括翻译起始因子2（eIF2α）α亚基磷酸化、激活转录因子4（ATF4）诱导以及已知下游靶点的表达增加。从机制上讲，奈非那韦介导的ISR绕过了eIF2α应激激酶的直接激活，而是依赖于对组成型eIF2α去磷酸化的抑制以及磷酸酶辅因子CReP（eIF2α磷酸化的组成型阻遏物；也称为PPP1R15B）的下调。这些发现表明，eIF2α特异性磷酸酶辅因子活性的调节可以是启动功能性ISR的细胞体内平衡的变阻器，并表明HIV-PIs可重新定位为人类疾病的治疗药物，以调节翻译速率和应激反应。
